Method and therapeutic system for smoking cessation

ABSTRACT

A method for treating conditions responsive to nicotine therapy, and particularly for smoking cessation therapy and for reducing nicotine craving, is described that utilizes transdermal nicotine delivery for obtaining base-line nicotine plasma levels coupled with transmucosal administration of nicotine to satisfy transient craving.

This is a continuation of application Ser. No. 08/221,914 filed Mar. 31,1994, now U.S. Pat. No. 5,593,684, which is a continuation of Ser. No.08/103,262, filed Aug. 4, 1993, now U.S. Pat. No. 5,362,496.

BACKGROUND OF THE INVENTION

This invention pertains to methods and therapeutic systems for treatinga condition responsive to nicotine therapy, and particularly for smokingcessation. More specifically, this invention is directed to methodscomprising the transdermal administration of nicotine, in combinationwith the transmucosal administration of nicotine to provide additionalperiodic doses of nicotine.

Nicotine replacement therapy as an aid to quitting smoking has beenbecome increasingly popular. Nicotine chewing gum (nicotine polacrilex)and transdermal nicotine are two of the more popular forms of nicotinereplacement available commercially. It has become clear, however, thatthe mere replacement of cigarettes with another nicotine source may notbe sufficient to insure success in smoking cessation therapy.Specifically, conventional nicotine replacement therapy does notadequately address the symptoms associated with the cessation ofsmoking.

Of the many smoking withdrawal symptoms, craving for cigarettes is oneof the most difficult to alleviate. As described in Steuer, J. D. andWewers, M. E. in Oncology Nursing Forum 1989, 16, 193-198, cigarettecraving is one of the most consistent, most severe, and earliestwithdrawal symptoms experienced by those attempting to quit smoking.Some reports suggest that craving peaks over the first 24 to 72 hours ofabstinence and then declines, although craving has been reported afterfive years of abstinence.

Research is focusing on the factors that precipitate craving in anattempt to better understand and deal with the problem of relapse. Someinvestigators believe that certain smokers are much more likely thanothers to experience craving symptoms, especially when trying to quitsmoking. Based on literature reports and his own investigations,Harrington (in Br. J. Soc. Clin. Psychol. 1978, 17, 363-371) reportedthat smokers can be separated by craving versus noncraving status, andthat these separate populations have different responses to smokingcessation therapy.

Most commercially available products for nicotine replacement in smokingcessation therapy have not specifically addressed the issue ofsatisfying craving for nicotine. Instead, as mentioned above, they havegenerally been targeted towards providing a stable baseline level ofnicotine in the blood. Some evidence indicates that low consistent bloodlevels of nicotine (as provided by transdermal nicotine, and to a lesserextent by nicotine gum) relieve some of the symptoms of nicotinewithdrawal, but craving symptoms may not be among these (see Russell, M.A. H. in Nicotine Replacement: a Critical Evaluation; Pomerleau, O. F.and Pomerleau, C. S., Eds.; Alan R. Liss, Inc.: New York, 1988; pp63-94). This may be because cigarette smoking provides an initial sharprise in blood level, which is missing in these nicotine replacementtherapies. The blood level peak produced by cigarettes is both higher(between 30-40 ng/mL) and sharper (this peak is attained within 10minutes) than the steadier levels obtained from polacrilex gum or atransdermal system. Russell states that the optimal steady-state bloodlevel for nicotine replacement is between 10-15 ng/mL, but thatquick-rise effects are probably necessary for more complete relief fromcraving in the early stages of cigarette withdrawal. His investigationssuggested that a rise in nicotine blood level of at least 10 ng/mL in 10minutes is required to obtain postsynaptic effects at nicotiniccholinergic receptors in the central nervous system and at autonomicganglia. These postsynaptic effects may be responsible for the feelingssuch as lightheadedness or dizziness experienced by cigarette smokers.See, also, Benowitz and Jacob (1984) Clin. Pharmacol. Ther. 36:265-270.

As mentioned above, nicotine gum (nicotine. polacrilex) is one of thecommercially available sources of nicotine for replacement therapy. Thisparticular nicotine gum is actually an ion-exchange resin that releasesnicotine slowly when the patient chews, and the nicotine present in themouth is delivered directly to the systemic circulation by buccalabsorption. However, much of the nicotine is retained in the gum throughincomplete chewing or is largely wasted through swallowing, so that thesystemic bioavailability of nicotine from this gum is low and averagesonly 30-40%. Moreover, compared with cigarette smoking, this form ofnicotine gum is a slow and inefficient source of nicotine. In addition,during ad libitum clinical or experimental use, the 2-mg gum producessteady-state blood nicotine levels that average around one third of theblood level peaks obtained from cigarette smoking. Thus, nicotine gum,when used alone, is frequently not effective as a method for smokingcessation.

Nicotine replacement through transdermal nicotine systems is anothertherapy that has become commercially available. These nicotine patchesprovide a low, consistent blood level of nicotine to the user, andbypass the first pass effects of the gut and liver. The concept ofapplying the teachings of transdermal drug therapy to the delivery ofnicotine has been described in the literature, and particularly in U.S.Pat. Nos. 4,839,174, 5,135,753, and U.S. Pat. No. 4,943,435, hereinincorporated by reference.

Nicotine is a suitable candidate for transdermal therapy because it isvolatile, highly lipid soluble, and permeates the skin easily. It is,however, a reactive liquid and a strong solvent. Therefore, transdermalnicotine systems must be made of materials that are compatible withnicotine and can release nicotine at a safe, useful flux. In addition,these systems should be designed to exploit the benefits of controlledrelease transdermal therapy. In general, one of the recognizedadvantages of transdermal therapy as opposed to other drugadministration techniques is the simplicity of the dosing regime.Another major advantage of continuous transdermal delivery is that theblood plasma levels of the delivered agent remain relatively steady. Inthis way, the periodic fluctuations between plasma levels above the safethreshold and below the efficacy threshold that are often seen with oraltablets or injections are eliminated, as are the "highs" associated withaddictive substances.

The primary use of transdermal nicotine systems to date has been forsmoking cessation therapy. A study by Rose, J. E. et al. (1985) Clin.Pharmacol. Ther. 38:450-456 demonstrated that systemic delivery ofnicotine in pharmacologically useful amounts was feasible by thetransdermal route. Studies using human cadaver skin in vitro arelikewise consistent with this finding. Typical permeabilities during thefirst day of patch use are on the order of 0.1 mg/cm² ·h, increasing to0.4 mg/cm² ·h and more at later times. Systemic absorption of 20 mg ofnicotine (approximately equivalent to smoking one pack of cigarettes)per day would then be theoretically achievable with a dermaladministration area of about 10 cm². This surface area is well withinthe range of appropriate sizes for transdermal delivery systems.

In addition, human clinical studies by Dubois et al. (1989) Meth. andFind. Exp. Clin. Pharmacol. 11:187-195, for example, have demonstratedthat application of transdermal nicotine systems results in nicotineblood levels on the order of 10-20 ng/mL, which is comparable to theminimum nicotine blood levels of moderately heavy cigarette smokers.Application of patches for 16 to 24 hours resulted in relativelyconstant blood levels in this range, indicating that the systems areuseful for reliable long-term delivery of nicotine.

Several groups of investigators have described clinical studies thatinvestigated efficacy and safety of transdermal nicotine systems forsmoking cessation. Abelin et al. (1989) The Lancet 1:7-10 reported onthe results of a double-blind study in which they determined thatlong-term use of a transdermal nicotine patch significantly increasedthe quit rate in cigarette smokers. The results of this study showedthat the number of abstainers in the transdermal nicotine group afterone, two, and three months of treatment was significantly greatercompared to the placebo group. In another study reported by Mulligan etal. (1990) Clin. Pharmacol. Ther. 47:331-337, the use of a transdermalnicotine patch in a 6-week placebo-controlled double-blind studyresulted in a significant degree of smoking cessation. Finally, a reportby Rose et al. (1990) Clin. Pharmacol. Ther. 47:323-330 of a randomizeddouble-blind trial indicates that certain smoking withdrawal symptomswere relieved by use of a transdermal nicotine system.

Therefore, transdermal nicotine systems can be designed to providehigher steady-state blood levels of nicotine, but are unable to provideblood level peaks or to provide a rapid increase in blood level. Thus,both nicotine gum and transdermal nicotine compete with each other asproducts providing steady-state nicotine blood levels, but do notsatisfy craving symptoms for cigarettes in some smokers.

Other nicotine replacement products that are on the market or have beenproposed in the literature have not been of serious interest in smokingcessation therapy, because of problems related to their use, and alsobecause of limited ability to satisfy craving for cigarettes. Nicotinevapor has been delivered to patients in aerosol form, similar to theinhaler technology used to supply bronchial asthma medications, and in a"smokeless cigarette" such as that marketed by Advanced Tobacco Productsunder the trade name Favor®.

Another smokeless version of nicotine delivered to the buccal mucosa isprovided by chewing tobacco, oral snuff, or tobacco sachets. Tobaccosachets, which are especially popular in Scandinavia and the U.S.,contain ground tobacco in packets that are sucked or held in the mouth.

The literature describes other capsules, tablets, and lozenges for oraldelivery of nicotine. For example, WO 803803 discloses a chewablecapsule filled with a liquid containing 0.1-10.0 mg of nicotine,together with additives for improving flavor and dispersion. Thecapsules are provided in a variety of pH values to allow the patient achoice of nicotine absorption rate, and are especially intended as anaid to quitting smoking.

Another nicotine capsule formulation is disclosed by M. E. Jarvik et al.(1970) Clin. Pharm. Ther. 11:574-576 for ingestion as a smokingcessation aid. These capsules, however, were apparently swallowed wholeby the subjects, according to the theory that intestinal absorption ofnicotine could produce significant blood levels. The study showed asmall but significant decrease in the number of cigarettes smoked bysubjects, but no quantitative measurements of nicotine blood levels wereobtained.

The literature also describes different designs of tablets fordelivering nicotine to the mouth and digestive system. BE 899037discloses a tablet containing 0.1 to 5 mg nicotine as a base orwater-soluble acid salt as an aid for quitting smoking.

Wesnes and Warburton (1984) Psychopharmacology 82:147-150; and (1986)Psychopharmacology 89:55-59 discuss the use of nicotine tablets inexperiments examining the effects of nicotine on learning andinformation processing. In the first experiment, nicotine was added todextrose tablets with a drop of tabasco sauce added to disguise thetaste of nicotine. In the second experiment, nicotine was added tomagnesium hydroxide tablets, under the theory that an alkalineenvironment in the mouth would enhance buccal absorption. Again, tabascosauce was added to the tablets to mask the taste of nicotine in bothactive and placebo tablets. The subjects were instructed to hold thetablets in the mouth for minutes before swallowing, in order to maximizecontact with the buccal mucosa.

Shaw (for example in GB 2142822 and U.S. Pat. No. 4,806,356) describes anicotine lozenge prepared from a mixture of inert filler material, abinder, and either pure nicotine or a nicotine-containing substance bycold compression. WO 9109599 describes a nicotine product for oraldelivery in the form of an inclusion complex of nicotine and acyclodextrin compound. The patent also discusses the use of variousexcipients and direct compression for manufacture of the product.

In recent years, several nicotine lozenges have been commercialized andare available as over-the-counter products in the U.K. Resolution®lozenges, manufactured by Phoenix Pharmaceuticals and distributed byErnest Jackson, contain 0.5 mg nicotine, together with the anti-oxidantvitamins A, C, and E. Stoppers® lozenges, distributed by Charwellpharmaceuticals Ltd., contain 0.5 mg nicotine and are available inchocolate, orange and peppermint flavors.

To date, it has been difficult to deliver nicotine in a profilemimicking the nicotine blood levels achieved by consistent smoking, tosatisfy cravings for nicotine in people who are attempting to quitsmoking, and thus, to provide greater protection against relapse thanother nicotine replacement therapies for people who are trying to quitsmoking. It is therefore desirable to provide improved compositions andmethods which avoid the disadvantages of these conventional nicotinedelivery devices and methods while providing an effective means fordelivering nicotine for smoking cessation treatment, for reducingnicotine craving, and for treating other conditions responsive tonicotine therapy.

SUMMARY OF THE INVENTION

The present invention consists of a method for treating a conditionresponsive to nicotine therapy, and particularly for smoking cessationtherapy and for reducing nicotine craving, comprising the steps of:

i) a first treatment with nicotine by transdermal administration toobtain nicotine blood levels of between 5 to 35 ng/mL for at least 12hours; and

ii) a second treatment with nicotine by transmucosal administration toobtain maximum nicotine blood levels from 2 to 20 minutes after thetransmucosal administration; and

wherein the transmucosal administration provides transient blood levelsof nicotine about 5 ng/ml above that provided by the transdermaladministration of nicotine.

In a preferred embodiment, the transmucosal administration results inmaximum nicotine blood levels from about 2 to 30 minutes, preferablyfrom about 2 to 20 minutes, and more preferably from about 2 to 10minutes, after the transmucosal administration of nicotine and isobtained by allowing a nicotine lozenge to completely dissolve in themouth. According to a particularly preferred embodiment, the nicotinelozenge will comprise nicotine, an absorbent excipient, such as mannitolor β-cyclodextrin, and a nonnutritive sweetener, such as xylitol,optionally in combination with ammonium glycyrrhizinate.

According to other embodiments, the transmucosal administration ofnicotine is obtained through the use of a nicotine containing gum,nicotine sublingual tablets or capsules.

The transdermal administration of nicotine is preferably obtained byadministering a transdermal system comprising:

(a) a nicotine depot layer, having a skin-facing side and a skin-distalside, the depot layer containing a sufficient quantity of nicotine tomaintain a useful flux of nicotine from the patch for a total timeperiod of 12 hours or more;

(b) an occlusive backing layer in contact with and covering the depotlayer on the skin-distal side; and

(c) rate-controlling means for controlling diffusion of nicotine fromthe skin-facing side at a first flux of greater than zero but less than2 mg/cm² in any hour for a first time period of greater than zero butless than 5 hours, then at a second flux between 20 and 800 mu g/cm² ·hfor a second time period of 7 hours or more.

According to other embodiments, the patch may take the form of areservoir system, in which the depot of nicotine is separated from theskin by a nonporous polymeric membrane, through which the nicotinediffuses at a controlled rate. The patch may also be in the form of amonolithic matrix, consisting of a single phase solution or mixture ofnicotine in a polymeric material, and wherein the nicotine is releasedby diffusion through the solution. A third possible embodiment involvesa combined system from which nicotine is released by a combination ofdiffusion through a polymeric solution, and diffusion across a polymericmembrane. Embodiments employing a monolith of nicotine in a polymericcarrier are particularly preferred.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of average nicotine plasma levels (nanograms(ng)/milliliter (mL)), resulting from use of cigarettes, tobaccosachets, or nicotine gum, as a function of time (minutes).

FIG. 2 shows an embodiment of the invention including an impermeablebacking (2) and a monolithic nicotine-containing matrix (3).

FIG. 3 shows an embodiment of the invention including an impermeablebacking (2), a nicotine depot (5), and a rate-controlling polymermembrane (6).

FIG. 4 shows an embodiment of the invention including an impermeablebacking (2), a monolithic nicotine-containing matrix (3), and a polymermembrane (8).

FIG. 5 is a graph of total nicotine release (milligrams (mg)/squarecentimeter (cm²)) against time (hours (hr)) for a polyurethane/nicotinemonolith.

FIG. 6 is a graph of nicotine delivery (mg/cm²) through 100-micron thickElvax 880 membranes, from a patch containing 200 mu L pure nicotine,with a membrane area of 4.5 cm², as a function of time (hr).

FIG. 7 is a graph of nicotine delivery (mg/cm²) through 100-micron thickElvax 88 membranes, from a patch containing 200 mu L of a 5% suspensionof nicotine in a 20 wt % sodium sulfate solution, with a membrane areaof 4.5 cm², as a function of time (hr).

FIG. 8 is a graph of nicotine delivery (mg/cm²) from patches with nylonor polyethylene membranes, as a function of time (hr). The nicotinecontent is 20-25 mg, and the patch area is 3.9 cm².

FIG. 9 is a graph of nicotine delivery (mg/cm²) from mixedmonolith/membrane patches containing a 50% nicotine load, using apolyethylene membrane or a polyethylene medical tape, as a function oftime (hr).

FIG. 10 is a graph of nicotine delivery (mg/cm²) from mixedmonolith/membrane patches containing a 40% nicotine load, using apolyethylene membrane or a polyethylene medical tape, as a function totime (hr).

FIG. 11 is a graph of nicotine delivery (mg/cm²) from mixedmonolith/membrane patches of various nicotine loads and sizes, using adouble-sided adhesive that contains a polyethylene membrane, as afunction of time (min).

FIG. 12 is a graph of nicotine plasma levels (ng/mL) after applicationof a transdermal nicotine systems with varying application areas, as afunction of time (hr).

FIG. 13 is a graph of the disintegration/dissolution profiles (weight %dissolved) of three different lozenge formulations, each containing 1 mgnicotine, as a function of time (minutes).

FIG. 14 is a graph of blood plasma levels (ng/mL) after application ofthe transdermal nicotine systems of the present invention deliveringeither 22 mg (□) or 27 mg (◯) of nicotine or the PROSTEP 22 mg (▪) patchas a function of time (hr) .

DESCRIPTION OF THE PREFERRED EMBODIMENT I. Terminology

Unless otherwise stated, the following terms used in the specificationand claims have the meanings given below:

"Transdermal system" means any system or device that is attached to theskin of a patient and is used to deliver a drug through the intact skinand into the patient's body.

"Transmucosal administration" or "transmucosal delivery" means anysystem or device for the administration of a drug across a patient'smucosal membrane, including the oral mucosa, such as the buccal andsublingual mucosa, and other mucosal membranes, including rectal, nasal,and vaginal. See "Controlled Drug Delivery, Fundamentals andApplications", 2nd Ed., Robinson and Lee, eds., Chapter 1, "Influence ofDrug Properties and Routes of Drug Administration on the Design ofSustained and Controlled Release Systems", Li et al., Marcel DekkerInc.: New York, pp. 3-61 (1987).

"Nicotine" refers to nicotine free base, i.e., a compound having theformula: ##STR1##

"Nicotine salt" refers to any mono- or bis-pharmaceutically acceptableacid addition salt or metal salt of nicotine.

"Nicotine lozenge" refers to any lozenge, capsule, tablet, or otherdevice for buccal delivery of nicotine.

"Prolonged period" means about 12 hours or more.

"Monolith" means a single-phase combination of nicotine and a polymericcarrier.

"Nonnutritive sweetener" refers to a synthetic or natural substancewhose sweetness is higher than or comparable to sucrose and which mayhave properties such as reduced cariogenicity, health benefits fordiabetics, or reduced caloric value compared to sugars.

"Essential oil" refers to a natural oil with a distinctive scentsecreted by the glands of certain aromatic plants having terpenes as themajor component. Examples of essential oils include, but are not limitedto, citrus oils, flower oils (e.g., rose and jasmine), and oil ofcloves.

"Pharmaceutically acceptable acid addition salt" refers to those saltswhich retain the biological effectiveness and properties of the freebases and which are not biologically or otherwise undesirable, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like, and organicacids such as acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, menthanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. For a descriptionof pharmaceutically acceptable acid addition salts, see Bundgaard, H.,ed., (1985) Design of Prodrugs, Elsevier Science Publishers, Amsterdam.

"Pharmaceutically acceptable metal salt" refers to those salts whichretain the biological effectiveness and properties of the free bases andwhich are not biologically or otherwise undesirable, formed with alkalimetal ions such as sodium or potassium; alkaline earth metal ions suchas calcium and magnesium; and other metal ions such as zinc.

II. Overview

The present invention provides for methods for treating conditionsresponsive to nicotine therapy, and particularly for smoking cessationtherapy and for reducing nicotine craving, comprising the administrationof nicotine transdermally and transmucosally. More specifically, thepresent invention provides for transdermal nicotine systems and systemsfor the transmucosal administration of nicotine, used together, eithersequentially and/or concurrently and in any order, for this purpose, andall methods of use of these systems for this purpose, including but notlimited to the embodiments and methods described below.

III. The Transdermal Nicotine System

A. The Monolith System

A basic embodiment of the transdermal nicotine system described in thepresent invention is shown in FIG. 2. Referring now to this figure, thenicotine dispensing patch, 1, comprises an impermeable backing layer, 2,and a monolithic matrix layer, 3, which both serves as a depot for thenicotine, and controls the rate at which it diffuses to the skin.

1. The Backing Layer

The impermeable backing layer, 2, defines the non-skin facing, or skindistal, side of the patch in use. The functions of the backing layer areto provide an occlusive layer that prevents loss of nicotine to theenvironment, and to protect the patch. The material chosen shouldtherefore be nicotine resistant, and should exhibit minimal nicotinepermeability. The backing layer should be opaque, because nicotinedegrades when exposed to ultraviolet light. Ideally, the backingmaterial should be capable of forming a support onto which thenicotine-containing matrix can be cast, and to which it will bondsecurely.

A preferred material is polyester or aluminized polyester. Polyester hasa nicotine permeability less than 0.2 mu g·100 mu m/cm² ·h. Preferredbackings are polyester medical films, available for example from 3MCorporation as Scotchpak™ 1005 or 1109. While applicants believe thatthere are relatively few materials that are really sufficientlyimpermeable to nicotine to retain the nicotine load adequately duringstorage or use, other low permeability materials that might be triedinclude, for example, metal foil, metallized polyfoils, composite foilsor films containing polyester, Teflon (polytetrafluoroethylene) typematerials, or equivalents thereof that could perform the same function.As an alternative to casting the matrix directly on the backing, thepolymer matrix may be cast separately and later adhere to the backinglayer.

2. The Monolith Layer

The nicotine monolith layer, 3, comprises nicotine finely dispersed, orpreferably dissolved, in a polymer matrix. The monolith layer may beprepared as follows. First a solution of the polymer matrix material ismade. Nicotine, preferably liquid, is then added to the polymersolution, and the mixture is homogenized. The percentage by weight ofnicotine in the solution may be varied according to the desired loadingof the finished monolith. The upper limit on the amount of nicotine thatcan be incorporated is determined by the stability of the solution.Above about 50 weight percent nicotine, the monolith becomes a solutionof the polymer in nicotine, rather than nicotine in the polymer, anddepending on the polymer used, a point is reached where it is no longerpossible to cast a stable film, because the solution remains in gel formor fluid form after casting.

The monolith solution may be poured into a mold or cast alone or on thedesired backing material. The casting is then covered and left for thesolvent to evaporate at room temperature. After solvent evaporation, themonolith takes the form of a polymer film typically having a thicknessin the range of about 25 to 800 mu m. It will be appreciated that for agiven desired total nicotine load, the percentage loading may be variedby varying the monolith thickness. In embodiments where the monolith isformed apart from the backing layer, a backing may be provided, forexample, by attaching a layer of single-sided occlusive medical adhesivetape to one face of the cast film.

The total nicotine content of the monolith will be sufficient to provideone day's supply. This amount depends on the user's need for nicotine.As a rough guide, a delivered load somewhere between 5 mg and 50 mg maybe appropriate in smoking cessation therapy.! It is probably notdesirable to go above about 50 mg delivered nicotine content, because ofthe toxicity hazard, although in theory patches of this type with abigger load can be made. Also, the amount of nicotine in the patch asmade may exceed the delivered load because, as the patch becomesexhausted, there will be an insufficient concentration gradient toremove all the nicotine. Consequently, the activity of the patch mayfall below useful levels.

A feature of these monolith embodiments is that they provide a solutionto the problems of skin irritation and potential toxicity. The activityof nicotine on the skin will be representative of the concentration ofnicotine in the monolith. Thus a monolith with a nicotine content of 30wt % will exhibit the activity of a 30% solution, rather than purenicotine, on the skin, with consequent substantial reduction orelimination of skin irritation. The release mechanism for the nicotineis diffusion under a concentration gradient. Therefore, even if thepatch were to be ingested, the nicotine release would be still a gradualprocess, and the victim would not be exposed to a very large, toxic, orlethal unit dose. Systems where the nicotine is held in an absorbentmaterial, or mixed in with some other liquid or gel, do not have thisadvantage.

To ensure that a user cannot be exposed to a toxic dose when the patchis used correctly, the in vitro nicotine flux from the patch must staywithin certain limits. This is a much more critical issue with nicotinethan with most drugs, because nicotine is very skin permeable, verytoxic, and very irritating. The skin flux of nicotine is about 100-300mu g/cm² ·h. However, it should be appreciated that this is a veryapproximate figure. One of the recognized problems in the art is thatskin permeabilities can vary 20-fold or more between individuals andbetween different skin sites on the same individual. It is thus clearthat a patch with a large nicotine load must be able to control releaseof that load, such that the in vitro flux from the patch does not exceedabout 10 times, preferably about 5 times, and more preferably aboutequals, the average skin permeation rate. Of course, embodiments wherethe in vitro flux from the patch is less than the skin permeation rate,such that the systemic absorption is controlled primarily by the patchrather than the skin, are acceptable, so long as the systemic nicotinelevel can be sustained above the necessary minimum level for thatindividual's needs.

Acrylic adhesives are a preferred polymer for forming monolith filmsbecause they can accept a relatively high nicotine loading and stillretain good adhesive characteristics. Monsanto's GELVA Multipolymersolution 737 is an example of a particularly preferred acrylic adhesive.

Polyurethanes are also acceptable for forming the monolith films,because they have been found to form stable solutions with nicotine, andthey exhibit suitable nicotine permeabilities. The polyurethane used maybe a polyether, polycarbonate, hydrocarbon or polyester type.Polyether-type polyurethanes are preferred, because in general they aremore inert than polyester-types, and thus more appropriate forbiomedical use. Polyether-type polyurethanes are typically made byreacting a dihydroxy-terminated polyether oligomer (diol) with adiisocyanate according to the reaction:

    HO-R-OH+OCN-R'-NCO→(-O-R-OCONH-R'-NHCO).sub.n -

where R is an alkyl group of the polyether. This prepolymer is thenfurther reacted with another diol where R is small, for example,1,4-butanediol, to yield a thermoplastic, elastomeric polymer, theproperties of which can be tailored by adjusting the proportions ofpolyether and butane diols. Polymers of this type in grades approved formedical use may be purchased from Dow Chemical, Midland, Mich., underthe name Pellethane™. Different hardnesses are available; the softergrades are generally desirable in the present context because they areeasier to dissolve and handle. Solvents that may be used to dissolvepolyurethanes include tetrahydrofuran (THF), dimethylsulfoxide (DMSO),and N,N-dimethylformamide (DMF). It is usually desirable to make highlyconcentrated solutions of polyurethane in the solvent of choice, so thatthe quantity of solvent that has to be evaporated is minimized.

Other polymers that can exhibit equivalent monolith forming and nicotineflux characteristics are intended to be within the scope of the presentinvention. Examples that might be used, depending on the desirednicotine load, film thickness, etc. include methacrylate polymers suchas polymethyl methacrylate or polybutyl methacrylate, orethylene-acrylic acid polymers, or functional equivalents thereof.

3. The Adhesive Layer

In use, the patches of the present invention may be held in contact withthe patient's skin in a variety of ways, such as by means of a porous ornonporous overlay coated wholly or partly with adhesive, by an adhesivelayer between the patch and skin, or by an annulus of adhesive aroundthe periphery of the patch. Of course, the mixed reservoir/monolithembodiments with adhesive medical tapes do not require additionaladhesive.

If an adhesive layer is to be included as an integral part of the patch,the adhesive should be nicotine compatible and permit a useful nicotineflux. In addition, the adhesive should satisfy the general criteria foradhesives used for transdermal patches in terms of biocompatibility,ease of application and removal, etc.

Suitable adhesives for use in the practice of the invention includepressure-sensitive adhesives approved for medical use. Amine-resistanttypes are preferred, so that the adhesive will not be attacked by thenicotine. For example, acrylate-type adhesives with amine resistance canbe used. Alternatively, a range of silicone-based amine-resistantmedical adhesives is offered by Dow Corning under the trade name BIOPSA. The adhesive layer can be cast directly onto the skin-facing sideof the membrane or monolith as a thin film. Alternatively, medicaladhesive tape, with or without nicotine-flux controlling properties, maybe used.

4. The Peel Strip

Loss of nicotine from the patch after manufacture should be kept to aminimum. Normally, the skin-facing side of the patch will be coveredwith a peel strip until the patch is used. As stressed throughout,nicotine is volatile, and retention of the nicotine load within thepatch during storage requires that the outer patch layers be extremelynicotine-resistant and nicotine-impermeable. The peel strip thereforeshould possess the same properties as the backing layer, and the samematerials are preferred.

5. A Preferred Embodiment

According to a particularly preferred embodiment, the transdermalnicotine patch will comprise a rounded-rectangular, "skin tone" coloredpatch on a clear, rectangular release liner. More specifically, thepatch will comprise a flexible, occlusive film backing, a multilaminatematrix containing nicotine, a skin adhesive layer, and a protectiverelease liner. The nicotine matrix typically will comprise nicotine, ananti-oxidant, preferably butylated hydroxyl toluene (BHT), and anacrylate-based adhesive. The skin adhesive layer typically will comprisean acrylate-based, pressure-sensitive adhesive.

Typically, these patches will be produced by first producing a castingsolution of nicotine, a solubilized acrylic pressure-sensitive adhesive,and a preservative, such as an anti-oxidant. The casting solution isthen coated onto a backing material, for example a polyester filmlaminate, which is then passed through an oven where the adhesive isdried. The coated backing web is laminated onto a preparedadhesive/release liner laminate comprising acrylic resin adhesive solidsand a silicone-coated, polyester release liner. The final product isthen cut into individual patches. These patches can be individuallypackaged in heat-sealed laminate pouches.

B. The Reservoir System

Another embodiment of the invention is shown in FIG. 3. Referring now tothis figure, the nicotine dispensing patch, 4, comprises an impermeablebacking layer, 2, a nicotine reservoir, 5, and a polymer membrane, 6.The backing layer may be the same as that used for the monolithembodiment described above.

1. The Reservoir

The reservoir may take various forms, for example, pure nicotine,nicotine diluted with a liquid or gelled carrier, or nicotine containedwithin the pores of a microporous matrix. These reservoir systems aredistinguished from the monolith embodiments of FIG. 2 in that thefunction of the reservoir layer is to be a depot for the nicotine and tokeep it in good contact with the membrane layer. The reservoir layerdoes not contribute to any measurable extent to the rate-controllingmechanism. To discourage tampering with the patch, or misuse of thecontents, it may be desirable to mix the nicotine with other materialsas described in U.S. Pat. No. 4,597,961 to Etscorn, incorporated hereinby reference.

If the patch is to be loaded with a comparatively small quantity ofnicotine, then the nicotine can be conveniently kept in contact with themembrane layer by holding it in the pores of a microporous matrix.Applicants have found that a disk of microporous nylon can be used. Thedisk also decreases the user's risk of exposure to a high dose ofnicotine should the patch become accidentally ruptured.

2. The Membrane Layer

The polymer membrane layer, 6, is the rate-controlling means thatregulates the flux of nicotine from the patch to the skin. The criteriafor selection of a suitable material are those discussed in thebackground section above, namely resistance to attack by nicotine, andpossession of an appropriate permeability for nicotine. The polymerchosen should also be compatible with the other components, and workableby standard techniques that are used in fabrication of the patch, suchas casting or heat sealing.

Dense nonporous membranes have a substantial advantage over microporousmaterials. Microporous membranes release the contents of the patch bypore flow. Thus, in areas of the pores, the skin is exposed to rawnicotine. Also, in the case of a volatile liquid such as nicotine, flowthrough the pores occurs rapidly, so that the system is quicklyexhausted, and the skin is flooded with excess nicotine for the life ofthe patch. In contrast, diffusion of nicotine through a nonporous filmtakes place by dissolution of the nicotine in the film, followed bydiffusion under a concentration gradient. By selecting materials withsuitable permeabilities, and making a membrane of appropriate thickness,it is possible, as taught by applicant, to tailor systems that canrelease their nicotine load gradually over 12 or 24 hours in a safe,controlled fashion.

Furthermore, the solution/diffusion mechanism protects the patient'sskin from exposure to excess amounts of raw nicotine. Based on extensiveexperimentation, Applicants believe that preferred membrane polymers arelow, medium, or high density commercial polyethylenes. Particularlysuitable are the grades obtainable under the trade name Sclairfilm™ fromDuPont Canada or those from Consolidated Thermoplastics. The 3MCorporation also manufactures a line of polyethylene membranes facedwith adhesive tapes that are very suitable. Other possible membranematerials are polyamides, such as nylon 6,6, or some grades of ethylenevinyl acetate copolymers. Functional equivalents of these are intendedto be within the scope of the invention.

The membrane layer may be formed by preparing a solution of the chosenpolymer in an organic solvent, casting on a glass plate or in a mold,and drying to evaporate the solvent. The thickness of the finished filmis tailored to give the desired nicotine flux. In general, membranesused in transdermal patches have thicknesses ranging from about 5 mu mto about 200 mu m.

Alternatively, it may be possible to purchase the membrane already infilm form. This type of transdermal patch may be prepared byheat-sealing the backing to the membrane layer around the perimeter ofthe patch. The nicotine formulation may be added either before or afterheat sealing. If the formulation is added before heat sealing, it isconvenient to shape the backing so as to form a cavity for retention ofthe nicotine, or to gel the nicotine. If the formulation is incorporatedafter heat sealing, the nicotine may be injected into the pouch formedby the heat sealing process, and the injection hole sealed.

As discussed for the monolithic embodiments, the patches of the presentinvention may frequently be required to hold a total nicotine load thatis 50% or more of the lethal dose. It is therefore important that thepatches be able to control the nicotine flux to the skin within safelimits at all times. In this regard, reservoir-type embodiments have anadvantage over the monolith systems. The advantage is that, so long asundiluted nicotine remains in contact with the reservoir side of themembrane, the nicotine flux through the membrane remains relativelyconstant over the life of the patch.

Monolith-type embodiments, on the other hand, often exhibit a fallingflux with time, as the portion of the monolith closer to the skinbecomes depleted of drug. As discussed above, these kinds ofconsiderations matter more when dispensing nicotine than with many othersubstances. Suppose that a transdermal patch, tested in vitro, deliversa substantial fraction of its total drug load during the first fewhours, at a flux several times higher than the average skin permeationrate. The in vitro flux then falls off to levels that are well below theaverage skin permeation rate until the patch is exhausted. When thispatch is applied to the user, the skin will be saturated with drug andthe drug will pass through the skin at a rate determined by that user'sskin permeability.

Typically a "depot" of drug will build up in the skin, and the drug willgradually reach the systemic circulation from this depot. Individualswith unusually high skin permeabilities will build up a larger skindepot faster than those with low skin permeabilities. For drugs that areless toxic than nicotine, less irritating to the skin, and/or have muchlower skin permeabilities, this "skin depot" phenomenon may be perfectlyacceptable, or even preferable, since it tends to balance out thefalling flux from the patch.

Many transdermal patches currently available exhibit this effect andfunction satisfactorily in this way. However, for nicotine, thesituation is different. A patch that can avoid this high initial drugburst, with consequent skin irritation or risk of overdose, isdesirable. Any initial flux from the patch should not exceed a maximumof 2 mg/cm² h, and more preferably should not exceed 1 mg/cm² ·h. Anyflux this high should never be sustained for more than 4-5 hours, andpreferably should not be sustained for more than 1-2 hours. Depending onthe drug load, the skin permeability of the patient, and the drug fluxrequired, it may be easier to stay within this limit with areservoir-type patch. The risk of accidental overdose if the patch isdamaged or ingested, however, is minimized with monolithic embodiments.There will therefore be circumstances where one or the other type ofpatch is preferably indicated.

C. The Mixed Monolith Reservoir System

The embodiment shown in FIG. 4 exploits the advantages of both reservoirand monolith systems. Referring now to this figure, the nicotinedispensing patch, 7, comprises an impermeable backing layer, 2, amonolithic matrix layer, 3, and a polymer membrane layer, 8. The backingand monolith layers are selected and prepared as described for theembodiment of FIG. 2.

The membrane layer may be selected and prepared as described for theembodiment of FIG. 2. Alternatively, and preferably, the membrane layermay take the form of a double-sided medical adhesive tape, which may beconveniently be attached to the finished monolith on the skin-facingside. If the tape contains a polymer backbone material that offersresistance to nicotine permeation, then this adhesive layer may have anicotine permeability of the same order or less than the monolithmaterial, so that the adhesive layer serves as a thin membrane limitingflux of nicotine from the patch.

The system functions as a mixed monolith reservoir system, where thenicotine release characteristics depend both on the monolith layer andthe membrane polymer. The preferred tapes for use in this way are thosewith a polyethylene backbone, such as 3M-1509, a 75 mu m thick medicaltape containing medium density polyethylene, and 3M-1512, a 38 mu mthick polyethylene tape, both available from 3M Company. The additionalresistance to permeation created by the tape assists in holding thenicotine load in the patch and moderates the initial high drug flux.

This embodiment is particularly useful in cases where the percentagenicotine load of the monolith is high, say more than about 30 wt %, orwhere the total nicotine load is high, say 30 mg or more. Systems withthis amount of nicotine are more likely to exhibit a large burst effecton initial application to the patient's skin than those with lownicotine content. The additional resistance of the membrane/tape layeris useful in keeping the initial nicotine flux within therapeuticallyacceptable levels.

Other advantages associated with this embodiment include a nicotineactivity representative of the concentration of nicotine in themonolith, so that skin irritation and adhesive degradation areminimized. The risk of an overdose of nicotine is reduced, because themonolith cannot release its nicotine load in a single burst if the patchis damaged or even swallowed.

D. Other Embodiments

Other embodiments of the present invention will utilize the transdermalnicotine patches described, for example, in U.S. Pat. Nos. 4,597,961,5,004,610, 4,946,853, and 4,920,989, each of which is expresslyincorporated herein by reference. More specifically, according to oneembodiment, a transdermal nicotine patch similar to the PROSTEP.SM. willbe employed. This patch comprises, proceeding from the visible outersurface toward the inner surface attached to the skin, (1) a foam tapeand pressure-sensitive acrylate adhesive; (2) backing foil, gelatin, andlow density polyethylene; (3) nicotine-gel matrix; (4) protective foilwith well, and (5) release liner.

Alternatively, a nicotine patch similar to the Habitrol.SM. patch can beused. This patch comprises, proceeding from the visible outer surfacetoward the inner surface attached to the skin, (1) an aluminized-backingfilm; (2) a pressure-sensitive acrylate adhesive; (3) a layer containinga methacrylic acid copolymer solution of nicotine dispersed in a pad ofnonwoven viscose and cotton; (4) an adhesive layer similar incomposition to layer (2) above; and (5) a protective aluminized releaseliner.

Other embodiments will employ a nicotine patch similar to the Nicoderm®nicotine transdermal system, available from ALZA Corporation, Palo Alto,Calif. This patch is a multilayered rectangular film containing nicotineas the active agent. Proceeding from the visible surface toward thesurface attached to the skin are (1) an occlusive backing, e.g.,polyethylene/aluminum/polyester/ethylene-vinyl acetate copolymer; (2) adrug reservoir containing nicotine, typically in an ethylene-vinylacetate copolymer matrix; (3) a rate-controlling membrane, such aspolyethylene; (4) a polyisobutylene adhesive; and (5) a protective linerthat covers the adhesive layer and must be removed before application tothe skin.

E. Patch Specifications

The transdermal nicotine patch provides a base line or steady statenicotine level to the patient. The total amount of nicotine released bythe patch during the period of use will vary depending on the user'sbody size, history of exposure to nicotine, and response to treatment,but will be roughly in the range of 5-60 mg. In general, this dosagewill maintain the nicotine blood level at a baseline level of between 5to 35 ng/mL nicotine, and more preferably between 10-20 ng/mL, which isbelieved to be the preferred steady-state blood level for optimaltherapy in most patients.

General guidelines for patch design must ensure that the patient isprotected at all times from toxic doses of nicotine, and must alsoensure that the patient receives a dose of nicotine that will beeffective for smoking cessation therapy. The in vitro flux from anyindividual patch used for the intended therapy should remain below about800 mu g/cm² ·h, preferably below 600 mu g/cm² ·h, and more preferablybelow 400 mu g/cm² ·h during the life of the patch. Staying within theselimits ensures that a patient with unusually permeable skin can neverreceive a toxic dose.

The size of the patch will vary according to the amount of nicotine tobe delivered. To deliver 25 mg in a 24-hour period, the patch would havea skin-contacting area of about 15-30 cm². To maximize patientacceptance and compliance, and to minimize any skin irritation, thepatch size should not exceed about 45 cm² maximum skin covering area.With the systems and release characteristics taught by applicant, itshould be possible to keep the patch size in the range 1-50 cm²,preferably 20-35 cm².

IV. The Transmucosal Administration of Nicotine

The present invention provides for the transmucosal administration ofnicotine, before, during, or after the transdermal delivery of nicotine.Transmucosal administration includes the delivery of nicotine throughthe oral mucosa, such as the sublingual and buccal mucosa, as well asthrough other membranes, including rectal, vaginal, and nasal membranes.These latter routes of administration are commonly used alternatives tooral administration, as they avoid the potential inconveniences of oraldrug delivery, such as a patient's inability to swallow andgastrointestinal side effects, and they offer direct access to the siteof absorption, thereby generally increasing the rate and extent ofabsorption.

Moreover, rectal drug administration has the advantage of minimizing oravoiding hepatic first pass metabolism, thereby increasing a drug'sbioavailability. However, systemic bioavailability for rectal dosageforms does seem to depend on a number of factors, including the site ofabsorption in the rectum and rectal motility. Similarly, delivery ofdrugs by the nasal route offers an attractive alternative to oraladministration by virtue of the relatively rapid drug absorption,possible bypassing of presystemic clearance, and relative ease ofadministration. Intravaginal drug administration offers the advantagesof minimized systemic side effects and rapid drug absorption. Therefore,drugs administered intravaginally have increased bioavailability overtheir orally administered counterparts, because of a reduced first passmetabolism.

A. Delivery through the Oral Mucosa

According to a particularly preferred embodiment, transmucosaladministration of nicotine will comprise oral administration (i.e,sublingual and buccal). This form of drug delivery provides for anefficient entry of active substances to the systemic circulation andreduces immediate metabolism by the liver and intestinal wall flora.Oral drug dosage forms (e.g., lozenge, capsule, gum, tablet,suppository, ointment, gel, pessary, membrane, and powder) are typicallyheld in contact with the mucosal membrane and disintegrate and/ordissolve rapidly to allow immediate systemic absorption. This termincludes, but is not limited to, lozenges, capsules, tablets, and gum.

The methods of manufacture of these formulations are known in the art,and include but are not limited to, the addition of the pharmacologicalagent to a pre-manufactured tablet; cold compression of an inert filler,a binder, and either a pharmacological agent or a substance containingthe agent (as described in U.S. Pat. No. 4,806,356); and encapsulation.Another oral formulation is one that can be applied with an adhesive,such as the cellulose derivative, hydroxypropyl cellulose, to the oralmucosa, for example as described in U.S. Pat. No. 4,940,587. This buccaladhesive formulation, when applied to the buccal mucosa, allows forcontrolled release of the pharmacological agent into the mouth andthrough the buccal mucosa.

Preferably, the orally administrable nicotine formulation of the presentinvention will consist of any lozenge, tablet, capsule, or gumformulation that delivers nicotine rapidly through the oral mucosacavity, and preferably through the buccal and/or sublingual mucosa. Thenicotine form that is added or incorporated into the nicotineformulations may be pure nicotine or any compound thereof. The method ofmanufacture of these formulations may be any suitable method known inthe art, including but not limited to the addition of a nicotinecompound to premanufactured tablets; cold compression of an inertfiller, a binder, and either pure nicotine or a nicotine-containingsubstance (as described in U.S. Pat. No. 4,806,356, herein incorporatedby reference); encapsulation of nicotine or a nicotine compound; andincorporation of nicotine bound to a cation exchange resin, for example,as in a chewing gum (as described in U.S. Pat. Nos. 3,877,468 and3,901,248, herein incorporated by reference).

Another oral formulation that is disclosed in the present invention isone that can be applied with an adhesive, such as the cellulosederivative, hydroxypropyl cellulose, to the oral mucosa, for example asdescribed in U.S. Pat. No. 4,940,587. This buccal adhesive formulation,when applied to the buccal mucosa, allows for controlled release ofnicotine into the mouth and through the buccal mucosa.

In a particularly preferred embodiment, the orally administrablenicotine formulation is a nicotine lozenge that delivers nicotine to thebuccal cavity, comprising nicotine dispersed in an absorbent excipientand a nonnutritive sweetener. See U.S. Pat. No. 5,549,906, which ishereby incorporated by reference. The lozenge is preferably held from2-10 minutes in the mouth as it dissolves completely and releasesnicotine into the mouth, and the dissolved nicotine solution is held inthe mouth for as long as possible so that the nicotine is absorbedthrough the buccal mucosa.

In another preferred embodiment, the orally administrable nicotineformulation comprises a nicotine gum, for example, the nicotine gum thatis commercially available from Merrell-Dow of Cincinnati, Ohio under thetrademark Nicorette.

Nicotine is a heterocyclic compound that exists in both a free base anda salt form. The free base is extremely volatile and is absorbed readilythrough mucous membranes and intact skin. The major problems reportedfor products based on nicotine free base originate from the volatilityof the nicotine, its acrid, burning taste, the irritating sensation onthe mucous membranes, and the decomposition of nicotine in the presenceof oxygen. Previously, these problems have been alleviated, in part,through the use of nicotine's salt form, i.e., an acid addition salt ormetal salt.

Surprisingly, the orally administrable nicotine formulations describedherein can be produced from either the free base or a pharmaceuticallyacceptable acid addition salt thereof, or any combination thereof. In anexemplary embodiment, nicotine, i.e., the free base form of nicotine, isused to produce a nicotine lozenge.

In any formulation used, the orally administrable nicotine formulationcontains fairly low doses of nicotine, preferably less than about 5 mg,and most preferably from about 0.5 to 4.0 mg, and in the case ofnicotine lozenges or tablets, most preferably from about 0.5 to about2.0 mg, to avoid accidental overdosage by swallowing the formulationintact. In addition, high doses are not required because the purpose ofthe nicotine formulation is to provide a transient blood level peak ofnicotine.

Use of the orally administrable nicotine formulation will result intransient nicotine blood level peaks that are at least 5 ng/mL higher,and more preferably at least 10 ng/mL higher, than the consistentnicotine blood level provided by the transdermal nicotine system. Use ofthe orally administrable nicotine formulation will result in thistransient nicotine blood level peak from about 2 to 30 minutes,preferably from about 2 to 20 minutes, and more preferably from about 2to 10 minutes, after the oral formulation is placed in the mouth.

The orally administrable nicotine formulation preferably is buffered toaid in the oral absorption of nicotine. A preferred formulation is at apH of 6.8-11. Preferred buffered formulations will include sodiumcarbonate, sodium phosphate, calcium carbonate, magnesium hydroxide,magnesium carbonate, aluminum hydroxide, and other substances known tothose skilled in the art. The orally administrable nicotine formulationmay contain a candy taste, such as a mint or other flavor, to mask thetaste of nicotine.

B. The Nicotine Lozenge

1. The Absorbent Excipient

According to a particularly preferred embodiment, the nicotine isdispersed in an absorbent excipient to form a nicotine lozenge.Absorbent excipients are pharmaceutically acceptable substances that arecapable 1) of reducing the volatility of the nicotine, for example,through absorption or by the incorporation of nicotine, such as in aninclusion complex, and 2) of being compressed into a lozenge or tablet.Suitable absorbent excipients include, but are not limited to, mannitol;cyclodextrins, including α-, β-, and γ-cyclodextrin, as well asderivatives of cyclodextrins, such as trimethyl-β-cyclodextrin,dimethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, andhydroxypropyl-β-cyclodextrin; silica preparations, such as the syntheticsilica formulation marketed under the trade name Syloid™ by W. R. GraceLimited of North Dale House, North Circular Road, London; cellulosicmaterials, such as Avicel microcellulose manufactured by FMCCorporation; and other conventional binders and fillers used in the foodindustry, such as acacia powder, gelatin, gum arabic, and sorbitol.

According to some embodiments, the absorbent excipient will serve morethan one role in the lozenge formulation. For example, mannitol canfunction as both a nonnutritive sweetener and an absorbent excipient.Similarly, the absorbent excipient can serve as a flavorant, bufferingagent, lubricant, or other component of the lozenge.

The absorbent excipient is typically present in an amount between about5 and 25% by weight (wt %), preferably in an amount between about 5 and20 wt %, and more preferably in an amount between about 5 and 15 wt %.

In a preferred embodiment, the absorbent excipient comprises mannitol orβ-cyclodextrin.

2. The Nonnutritive Sweetener

The nicotine lozenge will also contain a nonnutritive sweetener. Sincenicotine has an acrid, burning taste, the choice of a sweetener for anicotine lozenge can be critical, for many patients do not find thetaste of nicotine palatable in lozenge form. Typically, a nonnutritivesweetener or more preferably, a combination of sweeteners will beutilized in the lozenges described herein.

A nonnutritive sweetener is a synthetic or natural sugar substitutewhose sweetness is higher than or comparable to with sucrose. Table Ilists examples of nonnutritive sweeteners and their relative sweetnessvalues.

                  TABLE I                                                         ______________________________________                                        Nonnutritive Sweeteners                                                       Sweetener  Sweetness.sup.1                                                                           Sweetener Sweetness.sup.1                              ______________________________________                                        Saccharin  400-500     Invert sugar                                                                            1.1-1.2                                      Cyclamate  30-40       Palantinose                                                                             0.4-0.5                                      Aspartame  100-200     Xylitol   1.0                                          Acesulfame  200        Sorbitol  0.5-0.6                                      Monellin   2500        Mannitol  0.4-0.6                                      Neohesperidine                                                                           1000        Maltitol  0.7-0.9                                      Palatinit  0.4-0.5     --        --                                           ______________________________________                                         .sup.1 Sucrose = 1.0                                                     

Thus, the nonnutritive sweetener should have a relative sweetness valuebetween about 0.4 and 2500, as compared with sucrose, more typicallybetween about 0.4 and 500, preferably between about 0.4 and 200, andmore preferably, between about 0.4 and 2. See Makinen (1988) Oral Health78:57-66, which is incorporated herein by reference.

In a preferred embodiment, the nonnutritive sweetener is alsononcariogenic. The cariogenicity of a substance is dependent upon itssusceptibility to fermentation by Streptococcus mutans and other oralmicroorganisms. Dental researchers have long recognized that fermentablesweeteners such as sucrose, glucose, starch, and corn syrup arecariogenic or caries causing. The polyol nonnutritive sweeteners, suchas xylitol, sorbitol, fructose, invert sugar, palantinose, mannitol,maltitol, palatinit, and ammonium glycyrrhizinate, however, aregenerally not fermented to any significant degree and are lesscariogenic than sucrose. See Olinger presented at the Interphex-USAConference/Exhibition, New York; May 8-11, 1990.

More specifically, the ability of xylitol to inhibit the development ofnew caries has been demonstrated in numerous in vitro and in vivostudies. For example, field trials of oral products containing xylitolhave suggested that substitution of sucrose by xylitol in products suchas chewing gum may aid in prevention of dental caries (see Soderling,E., and Scheinin, A., Proc. Finn. Dent. Soc. 1991, 87(2), 217-229).Studies have also revealed that when xylitol-containing confections areconsumed as part of a normal diet, in conjunction with accepted oralhygiene practices, new caries incidence is reduced by about 50% to ashigh as 80%. See Olinger supra.

Moreover, the literature suggests that nonnutritive sweeteners, andparticularly xylitol, may be useful as a sugar substitute for weightcontrol, (see U.S. Pat. No. 3,717,711), which is clearly a major concernfor people who are quitting smoking. In addition, xylitol as been shownto prolong gastric emptying and decrease food intake in humans. SeeShafer et al. (1987) Am. J. Clin. Nutr. 45:744-47. Likewise, becausexylitol is not metabolized as a sugar, it has value for use with peoplewho must restrict their sugar intake, such as diabetics (see Maukinen,K., Oral Health 1988, 78(9), page 60).

Xylitol also has a cooling effect when it dissolves in the mouth, due toits negative heat of solution. Xylitol's heat of solution is -36.6cal/g, compared to -28.9 cal/g for mannitol, -26.6 cal/g for sorbitol,and -4.3 cal/g for sucrose (see Olinger, P. M., presented at theInterphex. USA Conference/Exhibition, New York; May 8-11, 1990).Therefore, xylitol is an excellent choice for a sweetener and excipientin a lozenge that needs to be held in the mouth for an extended periodof time, and that needs to be taken frequently every day for maximumtherapeutic effect.

Frequently a combination of nonnutritive sweeteners will be used.According to one embodiment, a sweetener with temporal sensoryproperties similar to that of sucrose (i.e., an appearance time of about4 seconds and an extinction time of 13 seconds, e.g., some of the polyolsweeteners, saccharin, cyclamate and aspartame) will be combined with asweetener whose sweetness develops slower or persists longer. Forexample, ammonium glycyrrhizinate, a nonnutritive sweetener with aslight licorice taste, has a taste onset or appearance time of about 16seconds for ammonium glycyrrhizinate and a taste persistence orextinction time of 69 seconds. Dubois and Lee (1983) Chem. Sens.7:237-248. Other examples of nonnutritive sweeteners with temporalsensory properties different than that of sucrose include, but are notlimited to, neohesperidine dihydrochalcone (appearance time of 9 secondsand an extinction time of 40 seconds) and stevioside (appearance time of4 seconds and an extinction time of 22 seconds).

In a preferred formulation, the lozenge will contain a nonnutritive,noncariogenic sweetener, such as xylitol, sorbitol, fructose, invertsugar, palantinose, mannitol, maltitol, and palatinit, either alone orin combination with other nonnutritive sweeteners. More preferably,xylitol, either alone or in combination with a nonnutritive sweetenerhaving an extinction time longer than that of sucrose, such as ammoniumglycyrrhizinate, neohesperidine dihydrochalcone, or stevioside, will beused. In an exemplary embodiment, the nonnutritive sweetener willcomprise xylitol and ammonium glycyrrhizinate.

The nonnutritive sweetener is typically present in an amount betweenabout 50 and 90 wt %, preferably in an amount between about 70 and 90 wt%, and more preferably in an amount between about 80 and 90 wt %.

3. Other Ingredients

The lozenge preferably is a buffered formulation in order to aid inbuccal absorption of nicotine. A preferred formulation is at a pH ofabout 6-11, and preferably at a pH of about 7-9. Preferred bufferedformulations will include sodium carbonate, sodium bicarbonate, sodiumphosphate, calcium carbonate, magnesium hydroxide, potassium hydroxide,magnesium carbonate, aluminum hydroxide, and other substances known tothose skilled in the art, as well as combinations of the aforementionedsubstances. In a most preferred formulation, the lozenge will containsodium carbonate and bicarbonate as buffering agents.

The buffering agent(s) should be present in an amount sufficient toadjust the pH of the lozenge to between 6 and 11, typically, betweenabout 0.1 and 25% by weight (wt %), preferably in an amount betweenabout 0.1 and 10 wt %, and more preferably in an amount between about0.1 and 5 wt %.

In addition, the lozenge may contain a flavorant, for example, a candytaste, such as chocolate, orange, vanilla, and the like; essential oilssuch as peppermint, spearmint and the like; or other flavor, such asaniseed, eucalyptus, 1-menthol, carvone, anethole and the like, to maskthe taste of nicotine. See Hall et al. Food Technol. 14:488 (1960);15:20 (1961); 19:151 (1965); 24:25 (1970); 26:35 (1972); 27:64 (1973);22:56 (1973); 28:76 (1974); 29:70 (1974) 31:65 (1977); 32:60 (1978); and33:65 (1979), each of which is incorporated herein by reference. It mayalso contain tobacco flavor in order to reproduce some of the sensationof smoking for the user. A small amount of colloidal silica (less thanabout 1 wt %) typically is added to tablets containing tobacco flavor toaid in manufacturing.

Magnesium stearate and/or hydrogenated vegetable oil may also be addedto the formulation as lubricants. Typically, the lubricant will bepresent in an amount between about 0.1 and 25 wt %, preferably in anamount between about 0.1 and 10 wt %, and more preferably in an amountbetween about 0.1 and 5 wt %.

The lozenges described herein may also contain a variety of otheradditives. For example, pharmacologically active ingredients such assodium monofluorophosphate, sodium fluoride, dextranase, mutanase,hinokitiol, allantoin, aminocaproic acid, tranexamic acid, azulene,vitamin E derivatives, sodium chloride and the like can be added atneed. More specifically, since the effects of xylitol and fluoride ondental hygiene are additive, the former can significantly enhance theefficacy of traditional fluoride treatments. Thus, according to oneembodiment, fluoride, and more particularly sodium monofluorophosphateor sodium fluoride will be incorporated into a lozenge formulationhaving xylitol as a nonnutritive sweetener.

In addition, the lozenge may be colored with conventional,pharmaceutically acceptable food coloring agents. Other additives thatmay be incorporated within the lozenges described herein include, butare not limited to, preservatives, antimicrobial agents, andantioxidants.

4. The Method of Manufacture

The method of manufacture of these lozenges may be any suitable methodknown in the art, including but not limited to, the addition of anicotine compound to premanufactured tablets; cold compression of aninert filler, a binder, and either pure nicotine or anicotine-containing substance (as described in U.S. Pat. No. 4,806,356,herein incorporated by reference); and encapsulation of nicotine or anicotine compound. See U.S. Pat. No. 5,135,753, herein incorporated byreference, for examples of methods of manufacture of various nicotinelozenges, sublingual tablets, and gelatin capsules. In a preferredembodiment, the lozenges are formed using direct compression.

According to another embodiment, an in situ inclusion complex is createdwith nicotine and β-cyclodextrin using a kneading technique.Specifically, a small amount of a nicotine-water solution is added tocyclodextrin and kneaded or mixed. See Szezetli in Cyclodextrins andTheir Inclusion Complexes, Akademiai Kiado: Budapest, 1992; p. 109;herein incorporated by reference. This method of forming thenicotine-cyclodextrin inclusion complex is preferred as it minimizes theuse of solvents or diluents and thus, eliminates a purification step inthe manufacturing process.

A further embodiment of the present invention provides for theproduction of inclusion complexes of both the nicotine and theflavorant. This embodiment is employed, for example, when an essentialoil, or other volatile flavorant, such as carvone or menthol, is used inthe lozenge formulation. As in the case of the nicotine inclusioncomplexes described herein, incorporation of the flavorant intocyclodextrin decreases the volatility of the flavorant and increasesformulation stability. In addition, as the flavorant is slowly releasedfrom the complex during lozenge administration, the flavorant will"last" longer and thus, offset the acrid taste of the nicotine forlonger periods of time.

According to this embodiment, a mixture of the nicotine and theflavorant, and optionally water, is added to the cyclodextrin andkneaded. Alternatively, the nicotine inclusion complex and the flavorantinclusion complex can be prepared separately and then mixed prior tolozenge formulation.

According to another embodiment, a portion of the nonnutritivesweetener, preferably xylitol, is utilized to hard coat the nicotinelozenge. Traditional pan coating techniques can be employed. Typically,weight increases of approximately 35% can be accomplished in less thanthree hours. See, e.g., Olinger supra.

The lozenges may be packaged in such a manner as to aid in maintainingnicotine stability. Preferred packaging methods include strip laminationin a foil-like material such as Barex®, or packaging in blisters using aTeflon-like material such as Aclar®. See also, Hunt et al. (1991) U.S.Pat. No. 5,077,104.

The lozenges described herein will typically have a weight of betweenabout 70 and 1000 mg and will contain fairly low doses of nicotine,preferably less than 5 mg, and most preferably from 0.5 to 2.0 mg.

C. Nicotine Gum.

According to another embodiment, the orally administrable nicotineformulation will comprise a nicotine chewing gum capable of rapidlydelivering nicotine to the oral cavity. One example of such a nicotinegum is Nicorette which is available in two strengths of 2 mg or 4 mg ofnicotine bound to an ion-exchange resin and incorporated into a gumbase. Release is controlled by the rate and vigor of chewing. The gum isintended to release nicotine over 20-30 minutes in doses similar tothose taken by cigarette smokers. However, to produce the rapid releaserates suitable for the methods described herein, the nicotine gum shouldbe chewed rapidly and vigorously to produce the desired nicotine plasmalevels, i.e., those mimicking cigarette smoking. Other gum formulationsmay not require such a chewing rate to produce the desired plasmanicotine levels.

Specific examples of the compositions of this invention are set forthbelow.

D. Other Sites of Transmucosal Administration

For delivery to the nasal membranes, typically an aerosol formulationwill be employed. The term "aerosol" includes any gas-borne suspendedphase of nicotine which is capable of being inhaled into the bronchiolesor nasal passages. Specifically, aerosol includes a gas-borne suspensionof droplets of the compositions containing nicotine, as may be producedin a metered dose inhaler or nebulizer, or in a mist sprayer. Aerosolalso includes a dry powder composition of a nicotine compositionsuspended in air or other carrier gas, which may be delivered byinsufflation from an inhaler device, for example.

For solutions used in making aerosols, the preferred range ofconcentration of the nicotine is 0.1-100 milligrams (mg)/milliliter(mL), more preferably 0.1-30 mg/mL, and most preferably, 1-10 mg/mL.Usually the solutions are buffered with a physiologically compatiblebuffer such as phosphate or bicarbonate. Typically, sodium chloride isadded to adjust the osmolarity to the physiological range, preferablywithin 10% of isotonic. Formulation of such solutions for creatingaerosol inhalants is discussed in Remington's Pharmaceutical Sciences,see also, Ganderton and Jones, Drug Delivery to the Respiratory Tract,Ellis Horwood (1987); Gonda (1990) Critical Reviews in Therapeutic DrugCarrier Systems 6:273-313; and Raeburn et al. (1992) J. Pharmacol.Toxicol. Methods 27:143-159.

Solutions of the nicotine containing compositions can be converted intoaerosols by any of the known means routinely used for making aerosolinhalant pharmaceuticals. In general, such methods comprise pressurizingor providing a means of pressurizing a container of the solution,usually with an inert carrier gas, and passing the pressurized gasthrough a small orifice, thereby pulling droplets of the solution intothe mouth and trachea of the animal to which the drug is to beadministered. Typically, a mouthpiece is fitted to the outlet of theorifice to facilitate delivery into the mouth and trachea.

For delivery to the rectal or vaginal mucosa, typically the nicotineformulation will comprise a suppository or be incorporated within avaginal sponge or tampon. Typically, the nicotine containing formulationwill be in a semisolid forms such as creams and suppositories. Thedosage form should disintegrate rapidly and permit contact of the drugwith the mucosa over a relatively large area to promote rapidabsorption.

E. Methods for the Transmucosal Administration of Nicotine

Whereas the patch serves to provide a base line or steady state nicotinelevel, the transmucosal administration of nicotine provides periodictransient blood level peaks of nicotine as an aid in reducing symptomsof craving of nicotine. Typically, the transmucosal administration willbe utilized ad libitum by the patient to alleviate cravings for nicotineas they arise. Thus, this method provides for a means for the patient toself-titrate his administration needs.

Again, the desire or need for the transmucosal administration ofnicotine (comparable to the desire to smoke cigarettes) typically willvary during any given day and from day to day, as well as from patientto patient. The methods described herein allow the patient toself-administer nicotine in the amounts and at the times when he mostfeels the craving for nicotine. As nicotine craving is considered bysome to be the most consistent and most severe factor in preventing aperson from quitting smoking, this ability to self-titrate and thus,stave off the craving for nicotine will increase the efficacy of asmoking cessation program.

A variety of methods can be utilized to assess the craving for nicotine,including but not limited to, the nicotine craving test specified by theDiagnostic and Statistical Manual of Mental Disorders, Revised ThirdEdition (DSM-III-R) (see (1991) J. Am. Med. Assoc. 266:3133); theShiffman-Jarvik Craving Subscale (see O'Connell and Martin (1987) J.Consult. Clin. Psychol. 55:367-371 and Steur and Wewers (1989) ONF16:193-198, also describing a parallel visual analog test); West et al.(1984) Br. J. Addiction 79:215-219; and Hughes et al. (1984)Psychopharmacology 83:82-87, each of which is expressly incorporatedherein by reference.

A preferred nicotine craving scale comprises that specified inDSM-III-R. Supra. According to this scale, a subject is asked to ratethe severity of his craving for nicotine on a scale between 0 and 4,wherein 0 is none; 1 is slight; 2 is mild; 3 is moderate; and 4 issevere. Using the compositions and methods described herein, the subjectshould attain at least a one unit, and preferably at least a two unit,decrease in his craving for nicotine as measured by the protocol setforth in DSM-III-R from about 2 to 30 minutes after administration ofthe oral nicotine formulation. More preferably, the maximum reduction incraving for nicotine will occur from about 2 to 20 minutes, and morepreferably from about 2 to 10 minutes after administration of the oralnicotine formulation.

The Shiffman-Jarvik Craving Scale is a six-item, forced-choice,self-report tool that measures cigarette craving. Each item has sevenpossible responses which correspond to scores ranging from 1 (nocraving) to 7 (high craving). A mean score is obtained to determine therespondent's level of craving. A typical craving score measured 48 hoursafter the initiation of a smoking cessation program is between about 4and 5; while a two-week follow-up craving scale will typically bebetween about 3 and 4. Using the compositions and methods describedherein, the subject should attain at least a one unit, and preferably atleast a two unit, decrease in his craving for nicotine as measured bythe protocol set forth in the Shiffman-Jarvik Craving Scale from about 2to 30 minutes after administration of the oral nicotine formulation.More preferably, the maximum reduction in craving for nicotine willoccur from about 2 to 20 minutes, and more preferably from about 2 to 10minutes after administration of the oral nicotine formulation.

The "craving questionnaire" craving scale employs a five itemquestionnaire that asks subjects to rate how much they had been missingtheir cigarettes, how difficult it had been to be without cigarettes,how much they had been aware of not smoking, how pre-occupied they hadbeen with thinking about cigarettes, and how much they had craved theircigarettes. The subject responds to each question with a number between1 and 3, where 1 is low and 3 is high. The ratings are combined to givea single craving score. According to this craving scale, a combinedscore of between about 9 and 12 is typical. Using the compositions andmethods described herein, the subject should attain at least a threeunit, and preferably at least a four unit, decrease in his craving fornicotine as measured by the protocol set forth for use with this cravingquestionnaire from about 2 to 30 minutes after administration of theoral nicotine formulation. More preferably, the maximum reduction incraving for nicotine will occur from about 2 to 20 minutes, and morepreferably from about 2 to 10 minutes after administration of the oralnicotine formulation.

When the transmucosal administration of nicotine is accomplished throughthe oral mucosa, the nicotine formulations should be administeredwithout holding any other substance, such as food or beverage, in themouth. It is particularly important that acidic substances or beveragessuch as fruits, coffee, tea, or fruit juices are not consumedimmediately or concurrently with the oral nicotine formulations, inorder to insure that a basic environment is maintained within the mouth.

According to a particularly preferred embodiment, a nicotine lozenge ortablet is held from 2-10 minutes in the mouth as it dissolves completelyand releases nicotine into the mouth, and the dissolved nicotinesolution is held in the mouth for as long as possible so that thenicotine is absorbed through the buccal mucosa. According to anotherpreferred embodiment, a nicotine containing gum is vigorously chewed torelease nicotine into the oral cavity.

Example 39 describes a protocol for measuring nicotine blood levels inpatients following the transmucosal administration of nicotine. Thenicotine blood levels in these patient should closely mimic thetransient peak levels of a cigarette smoker. For example, use of thelozenge will result in transient nicotine blood level peaks that are inthe range of 15 to 35 ng/mL, and more preferably in the range of 20 to30 ng/mL.

The transmucosal administration of nicotine will result in thistransient nicotine blood level peak from about 2 to 30 minutes,preferably from about 2 to 20 minutes, and more preferably from about 2to 10 minutes, after the formulation is administered. For example, FIG.13 presents the disintegration/dissolution profiles of the threenicotine lozenge formulations described in Examples 34-36 (Formulation 1contains nicotine, mannitol, xylitol, mint flavor, and other excipients;Formulation 2 contains nicotine, mannitol, xylitol, tobacco flavor, andother excipients; and Formulation 3 contains nicotine, cyclodextrin,xylitol, and mint flavor). As shown in FIG. 13, lozenges formulatedaccording to the present invention will be at least 60% dissolved after3 minutes in the mouth, at least 80% dissolved after 5 minutes, andapproximately 100% dissolved after 10 minutes.

IV. The Transdermal and Transmucosal Administration of Nicotine

When smoking a cigarette, the smoker receives an initial burst ofnicotine into the bloodstream, which then rapidly declines. The urge tosmoke increases as the nicotine level continues to fall below a givenpoint in the blood level, a point which can vary with each smoker.However, it has been shown that the normal plasma trough levelassociated with normal smoking is approximately 5-15 ng/mL within onehour of first smoking. At the time of smoking the plasma level isbetween 15 ng/mL and 30 ng/mL and the natural urge to smoke is therebysuppressed. When nicotine levels fall to a level of 10 ng/mL or less,nicotine intake is required to suppress the smoking urge.

Although the nicotine plasma levels required to suppress smoking arefairly consistent between smokers, smokers vary widely in theirfrequency of smoking, i.e., how often the smoking urge occurs. Morespecifically, nicotine cravings depend, in part, upon daily stresspatterns, sleep and eating habits and body weight, previous smokinglevels, demographic factors, behavioral factors, race-ethnicity,culture, and the like. See Sachs and Leischow (1991) Clinics in ChestMedicine 12:769-791.

A subject's frequency of smoking can be quantified using aneight-question scale, termed the Fagerstrom Nicotine Tolerance Scale(see Fagerstrom (1978) Addict. Behav. 3:235-241 and Sachs (1986) Clinicsin Geriatric Medicine 2:337-362) which provides a relative index of thedegree of physical dependency that a patient has for nicotine. This testis shown below in Table II.

                  TABLE II                                                        ______________________________________                                        Fagerstrom Nicotine Tolerance Scale                                                           A      B         C                                            ______________________________________                                        How soon after you wake up do you                                                               After 30 Within 30                                          smoke your first cigarette?                                                                     min      min                                                Do you find it difficult to refrain                                                             No       Yes                                                from smoking in places where it is                                            forbidden, such as the library,                                               theater, doctor's office?                                                     Which of all the cigarettes you smoke                                                           Any other                                                                              The first                                          in a day is the most satisfying one?                                                            than the one in the                                                           first one                                                                              morning                                                              in the                                                                        morning                                                     How many cigarettes a day do you                                                                1-15     16-25     More                                     smoke?                               than 26                                  Do you smoke more during the                                                                    No       Yes                                                morning than during the rest of the                                           day?                                                                          Do you smoke when you are so ill                                                                No       Yes                                                that you are in bed most of the day?                                          Does the brand you smoke have a                                                                 Low      Medium    High                                     low, medium, or high nicotine                                                 content?                                                                      How often do you inhale the smoke                                                               Never    Sometimes Always                                   from your cigarettes?                                                         ______________________________________                                    

Points are assigned as follows: 0 points for each answer in column 1; 1point for each answer in column B; and 2 points for each answer incolumn C. The points are totaled to yield the nicotine tolerance scale.The highest possible score is 11. Patients who score 7 or more areconsidered to be highly dependent on nicotine. Patients who score lessthan 6 have a low nicotine dependence.

Thus, the objective for any smoking cessation therapy involving nicotineadministration should be the rapid attainment of the appropriatenicotine plasma levels at the necessary frequency of administration forthe individual patient, while sustaining a minimum steady state or baseline level of nicotine plasma level. The present invention fulfills thisobjective through the use of a transdermal nicotine patch in combinationwith the transmucosal administration of nicotine, and preferably theadministration of nicotine through the oral mucosa, and most preferably,with nicotine lozenges. The transdermal patch and the transmucosaladministration of nicotine operate in a complimentary manner with thetransdermal patch providing the steady-state systemic levels of nicotinein the bloodstream to which the smoker has become accustomed, whereasthe transmucosal administration of nicotine provides for the rapidattainment of the transient levels of nicotine that mimic cigarettesmoking and are required to alleviate nicotine craving.

Moreover, in contrast to previous smoking cessation therapies that canbe characterized as a "one size fits all" approach in that thesetherapies did not take into account the many factors which maycontribute to nicotine craving, the compositions and methods describedherein allow for an individualized approach to smoking cessationtherapy. Specifically, the total amount of nicotine delivered, thedelivery mode, i.e., via patch or transmucosal delivery method andregimen, i.e., the order of administration and duration of use of eitherthe patch and/or the transmucosal delivery formulation, can be varied totake into account the patient's needs, e.g., the therapeutic indication,the patient's age and body weight, and the degree of nicotine dependencydisplayed by the patient.

For example, according to one embodiment, the transdermal patch andtransmucosal administration of nicotine are first used concurrently andsimultaneously for a period of from about 3 to 12 weeks, and preferablyfrom about 4 to 8 weeks, followed by a period of from about 3 to 12weeks, preferably from about 4 to 8 weeks, and most preferably fromabout 4 to 6 weeks, in which only the patch or only the transmucosalnicotine formulation is used.

Other embodiments will employ different dosage levels of either thepatch and/or the transmucosal nicotine formulation to suit the needs ofthose patients with either a relatively high or low nicotine dependency.For example, a smoking cessation program for heavy smokers, i.e., thosesmokers having a score of 7 or more on the Fagerstrom test, willtypically consist of three phases. During the initial phase, a highdosage nicotine transdermal patch, typically, with a high loading ofnicotine in the range of about 30-60 mg, and preferably, about 40-45 mg,is administered for a period of from about 4 to 8 weeks. Typically,transmucosal administration of nicotine will be used in conjunction withthis high dosage patch. Subsequently, a transdermal patch with a lowerloading of nicotine, typically in the range of about 10-30 mg, andpreferably, about 20-25 mg, and again, the transmucosal administrationof nicotine will be used in combination for a period of from about 4 to8 weeks. Finally, for a period of from about 4 to 6 weeks, either thepatch or the transmucosal administration of nicotine may be used alone.

A similar smoking cessation program can be developed for the moderatesmoker, i.e., those scoring 6 or less on the Fagerstrom test. Forexample, during the initial phase, a transdermal patch with a moderateloading of nicotine, typically in the range of about 10-40 mg, andpreferably, about 25-30 mg, is administered in conjunction with thetransmucosal administration of nicotine. The second phase of thissmoking cessation program will consist of administration of a lowerdosage transdermal patch, typically containing nicotine in the range ofabout 10-30 mg, and preferably, about 20-25 mg, optionally, with thetransmucosal administration of nicotine, will be used for a period offrom about 4 to 8 weeks. During the final phase or weaning period,either the patch or transmucosal administration will be used alone.

Likewise, a smoking cessation program for the light smoker can bedeveloped using the compositions and methods described herein. Forexample, a transdermal patch containing a relatively low loading ofnicotine, typically containing nicotine in the range of about 10-30 mg,and preferably, about 20-25 mg, optionally, with the transmucosaladministration of nicotine, will be used for a period of from about 4 to8 weeks. During the final phase or weaning period, either the patch orthe transmucosal formulation will be used alone.

Of course, with some individuals, administration of the transmucosalformulation may be sufficient to reduce the strong desire for cigarettesmoking. Thus, and with many patients, it is possible to reduce theincidence of smoking with either the transdermal patch or thetransmucosal formulation alone.

Of course, the transdermal nicotine patches and the transmucosaladministration of nicotine can also be used according to a dosagepattern prescribed by a physician. The dosage pattern will vary with theindication. For example, in addition to use in smoking cessation orreduction therapy, the compositions and methods described herein can beused for the treatment of Alzheimer's Disease, ulcerative colitis andrelated conditions, and diseases associated with reduced centralcholinergic function, loss of cholinergic neurons, significant reductionin nicotine receptor binding, neurodegenerative dementia, or cognitionand memory impairment, and other diseases responsive to nicotinetherapy. See Masterson (1991) U.S. Pat. No. 5,069,904; Wesnes andWarburton (1984) Psychopharmacology 82:147-150; and Warburton et al.(1986) Psychopharmacology 89:55-59.

As will be evident from the previous discussion, the ability to measurethe patient's nicotine blood plasma levels can be of tremendous value intailoring a smoking cessation or other therapy to the patient's needs.There has been very little discussion in the literature of using director indirect measurement of nicotine blood levels as an integral part ofsmoking cessation therapy. The traditional interest in quantifyingnicotine blood levels has been related to research on efficacy ofsmoking cessation therapies. For example, research studies commonly usedvarious measurement techniques to attempt to verify self-reports ofsmoking frequencies by study subjects. These include the measurement insaliva and blood plasma of nicotine, cotinine (the primary metabolite ofnicotine), carboxyhemoglobin, and thiocyanate; and the measurement inexpired air of carbon monoxide. The most frequently cited technique isthe quantification of cotinine, a nicotine metabolite, in saliva. Thequantification of cotinine in blood fluids can be accomplished bygas-liquid chromatography, radioimmunoassay, and liquid chromatography.(For a discussion of liquid chromatographic assays for cotinine, seeMachacek and Jiang (1986) Clin. Chem. 32:979-982, herein incorporated byreferences.)

The present invention also comprises the direct or indirect measurementof nicotine blood levels as an integral part of methods for treatingconditions responsive to nicotine therapy, and particularly for smokingcessation therapy and for reducing nicotine craving. The nicotine bloodlevels can be measured before, during, or after the administration ofnicotine, either transdermally or transmucosally, as an aid indetermining the amount of nicotine to be administered and the frequencyof administration. In a preferred embodiment, saliva samples are takenfrom the patients and used for measurement of cotinine, as a biochemicalmarker of nicotine blood plasma levels. Cotinine levels are determinedusing any of the analytical methods known to those skilled in the art.In a particularly preferred embodiment, the cotinine assay would beportable and easily and simply accomplished by the patient, as in anassay kit or strip indicator.

The invention is now further illustrated by Examples 1 to 40, which areexemplary but nonlimiting.

EXAMPLES 1-7 Monolith Embodiments Example 1

Monolithic patches were made as follows. A solution of nicotine-loadedadhesive was made by mixing a liquid adhesive/solvent solution (GELVA737, Monsanto Corp.), 12.36 wt % liquid nicotine and 0.25 wt % BHT andagitating the resulting solution on a bottle roller for 12 hours. A 2 mLlayer of the above solution was then coated onto the backing material(Scotchpak 1109) using a knife over roll coating head. Thecoated-backing was then passed through an oven at temperatures from50°-55° C. at a speed of 5 ft/min for a total dwell time of 3 minutes.Patches with an area of 20 cm² were cut from the finished matrix with arotary die punch.

Example 2

Monolithic patches were made by the procedure as described in Example 1,except that the amount of liquid nicotine was increased to 15.05 wt %.

Example 3

Monolithic patches were made as follows. A solution of nicotine-loadedPellethane™ 2363-80AE was made by mixing Pellethane pellets intotetrahydrofuran, adding 10 wt % liquid nicotine, and agitating on abottle roller for three days. A layer of backing material grade 3M-1005was spread in a petri dish and covered with the matrix mixture. Thepetri dish was covered, and the matrix was left for the solvent toevaporate at room temperature. Patches with an area of 3.88 cm² were cutfrom the finished matrix with a punch.

Example 4

Monolithic patches were made and tested by the same procedure asdescribed in Example 3, except that the nicotine content of the matrixmixture was 17 wt %.

Example 5

Monolithic patches were made and tested by the same procedure asdescribed in Example 3, except that the nicotine content of the matrixmixture was 23 wt %.

Example 6

Monolithic patches were made and tested by the same procedure asdescribed in Example 3, except that the nicotine content of the matrixmixture was 33 wt %.

Example 7

Monolithic patches were made and tested by the same procedure asdescribed in Example 3, except that the nicotine content of the matrixmixture was 50 wt %.

Example 8

The physical characteristics for two particularly preferred nicotinetransdermal patches of the present invention are shown below in TableIII.

                  TABLE III                                                       ______________________________________                                        Property       Low Dosage Patch                                                                           High Dosage Patch                                 ______________________________________                                        Dosage Strength                                                                              22 mg/20 cm.sup.2                                                                          27 mg/20 cm.sup.2                                 Size (cm.sup.2)                                                                              20           20                                                Nicotine content (mg)                                                                        31.4         37.7                                              24 Hour Delivery (mg).sup.2                                                                  22           27                                                Flux (mg/cm.sup.2 /24 hour).sup.3                                                             1.1          1.35                                             Total Nicotine Delivered (%)                                                                 73           75                                                Patch Weight (mg)                                                                            837          843                                               Thickness (microns)                                                                          333          344                                               ______________________________________                                         .sup.2 Based on residual content from in vivo performance.                    .sup.3 Estimated from in vivo performance.                               

The compositions of two particularly preferred nicotine patches areshown below in Table IV.

                  TABLE IV                                                        ______________________________________                                        Composition      Nicotine Patch A                                                                          Nicotine Patch B                                 ______________________________________                                        Dosage           22 mg/20 cm.sup.2                                                                         27 mg/20 cm.sup.2                                Nicotine content (mg)                                                                          31.4        37.7                                             Acrylic adhesive matrix (mg)                                                                   70.2        70.2                                             Butylated hydroxytoluene (mg)                                                                  0.6         0.6                                              Polyester film laminate (mg)                                                                   76.0        76.0                                             Acrylate skin adhesive (mg)                                                                    358.0       358.0                                            Polyester release liner (mg)                                                                   302.4       302.4                                            Total (mg)       837.2       843.2                                            ______________________________________                                    

Example 9 Membrane Flux Tests

Promising membrane polymers that appeared to be able to withstandnicotine were tested for their nicotine permeability. The experimentalprocedure in each case was as follows. Samples of the films were mountedin teflon flow-through diffusion cells. Buffered isotonic saline wascirculated through the bottom of the cell. Membrane samples were mountedon the bottom of each cell fixed by the threaded neck that also acts asthe drug solution reservoir. The exposed area of the membrane was 3.9cm². The membrane permeability was measured by the rate of permeation ofnicotine into the saline solution. The samples were:

Dartek™ F101: nylon 6,6

Sclairfilm™ HD-2-PA: high density polyethylene

Sclairfilm™ LWS-2-PA: medium density polyethylene

Hytrel™ 5556: polyester elastomer

B410: high density polyethylene

ELVAX™ 880: ethylene/vinyl acetate copolymer, 7.5 wt % vinyl acetate

Saran™ 18L: polyvinylidene chloride

The results are summarized in Table V⁴.

                  TABLE V                                                         ______________________________________                                                                          Nicotine                                                                      Permeability                                             Thickness Nicotine Flux                                                                            (μg · 100 μm/                Membrane     (μm)   (μg/cm.sup.2 · hr)                                                           cm.sup.2 · hr)                     ______________________________________                                        Dartek ® F101                                                                          78        20         16                                          Sclairfilm ® HD-2-PA                                                                   22        60         27                                          Sclairfilm ® LWS-2-PA                                                                  50        45         22                                          Hytrel ® 5556                                                                          250       10         25                                          B410         50        20         10                                          ELVAX ® 880                                                                            100-150   >200       >200                                        Saran ® 18L                                                                            50        16          8                                          ______________________________________                                    

Example 10-14 Reservoir Embodiments Example 10

Experimental patches were made by heat sealing a backing of Scotch™ 1006composite polyester tape to a 100- mu m thick film of Elvax 880. Theresulting pouches were filled with approximately 200 mu L of nicotine,and the injection hole covered with a plug of hot melt glue. Thefinished characteristics of the patches were tested by the proceduredescribed in Example 3, and the nicotine was released into saline at 37°C. The patches exhibited very high initial fluxes of the order 2 mg/cm²·h. Half the nicotine load was delivered within the first 15-20 hours.

Example 11

The patch-making procedure and release tests described in Example 9 wererepeated using the same membrane, but with a load of 200 mu L of 20 wt %sodium sulfate solution containing a 5% suspension of nicotine. Thepatches exhibited a very high initial drug burst, followed by an averageflux of about 8.5 mu g/cm² ·h for the rest of the test period.

Example 12

Experimental patches containing a disc of microporous nylon were made. Adisc having an area of 3.9 cm² was punched from a sheet of microporousnylon 6,6. The disc was glued to a nonporous 78- mu m thick film ofDartek F101. The disc was wetted with nicotine. The disc could holdabout 20-25 mu L of nicotine. The membrane/disc assembly was heatedsealed to a backing of Scotch 1006 or 1220 composite polyester tape. Thefinished patches had an effective membrane area of 3.9 cm². The releasecharacteristics of the patches were tested by the procedure described inExample 3. The flux from these patches was about 10 mu g/cm² ·h duringthe first 10 or 15 hours, rising to about 20 mu g/cm² ·h after about20-25 hours.

Example 13

The patch-making procedure and release tests described in Example 11were repeated with a 22- mu m thick film of Sclairfilm HD-2-PA as themembrane. The flux from the patch remained roughly constant at about 80mu g/cm² ·h for the first 60 hours, falling to about 30 mu g/cm² ·hthereafter.

Example 14

The patch-making procedure and release tests described in Example 11were repeated with a 50- mu m thick film of Sclairfilm HD-2-PA as themembrane. The flux from the patch remained roughly constant at about45-50 mu g/cm² ·h.

Examples 15-20 Mixed Monolith/Membrane Systems

Monoliths containing 50% nicotine were made by the same generalprocedure as described in Example 3. For Example 14, a membrane of 100-mu m thick Sclairfilm HD-2-PA was cast onto the monolith. For Example15, a 38- mu m thick membrane of polyethylene grade HD-106 obtained fromConsolidated Thermoplastics was cast onto the monolith. For Examples 16and 17, the membranes of Examples 14 and 15 were coated with a 25- mumthick layer of BIO PSA grade X7-2920. For Example 18, the monolith wascoated with polyethylene, double-sided, medical adhesive tape grade3M-1509. For Example 19, the monolith was coated with polyethylene,double-sided, medical adhesive tape grade 3M-1512.

Release tests were carried out as with the previous examples. The uppercurve shows the nicotine release from the monolith loaded with 50%nicotine without any membrane or adhesive. As can be seen, the presenceof the membrane or membrane tape brings the steady-state flux down to 50mu g/cm² ·h or less.

Examples 21-24

Monoliths containing 40% nicotine were made by the same generalprocedure as described in Example 3. For Example 20, the monolith wascast with the blade height set at 1,000 mu m. For Example 21, themonolith was cast with the blade height set at 1,500 mu m. For Example22, the monolith was cast with the blade height set at 2,000 mu m. ForExample 23, the monolith was cast with the blade height set at 2,500 mum. All monoliths were covered with 3M-1512 medical tape. Release testswere carried out as for the previous examples. A more pronounced bursteffect was observed with the thicker monoliths, containing morenicotine. The 1,500 mu m cast monolith maintained an average flux ofabout 500 mu g/cm² ·h for 24 hours, and released a total of about 4mg/cm² in the first 5 hours. The 1,000 mu m cast monolith maintained anaverage flux of about 120 mu g/cm² ·h for 24 hours, and released a totalof about 1.5 mg/cm² in the first 5 hours.

Examples 25-28

Monoliths containing varying loads of nicotine were made as follows. Asolution of nicotine-loaded Pellethane 2363-80AE was made by mixingPellethane tablets and 12 wt % nicotine into tetrahydrofuran in a sealedmixing vessel. The solution was stirred for four hours. The backingmaterial grade 3M #1109 was then coated on a knife over roll coater, andthe solvent was driven off in three successive ovens at 24° C., 35° C.,and 36° C., respectively. The cast film was then laminated to 3M MSX100/75, which is a double-sided adhesive that consists of an adhesivelayer, a polyethylene membrane, a second adhesive layer, and a releaseliner.

For Example 24, the monolith contained 37 mg of nicotine, with a patcharea of 5 cm². For Example 25, the monolith contained 74 mg of nicotine,with a patch area of 10 cm². For Example 26, the monolith contained 60mg of nicotine, with a patch area of 20 cm². For Example 27, themonolith contained 54 mg of nicotine, with a patch area of 30 cm².

Device release rate measurements were made as follows. Each transdermalsystem was attached to the disk assembly, adhesive side up, of a USPDissolution Bath, as described in The U.S. Pharmacopeia XXII, TheNational Formulary XVII; U.S. Pharmacopeial Convention, Inc.: Rockville,Md., 1989; pp 1578-1583, herein incorporated by reference. The diskassembly was placed inside the dissolution vessel, which contained 500mL of degassed, deionized water maintained at a constant temperature of32+/-0.5° C. The paddle was operated at a constant rate of 50 rpm at25+/-2 mm from the surface of the disk assembly. Periodic samples weretaken for HPLC analysis using a Dionex PCX-500 reverse-phase/ionexchange column. As shown, nicotine release per unit area is verysimilar for Examples 24 and 25, which have identical nicotine loadingsof 7.4 mg/cm². For Examples 26 and 27, nicotine release per unit areadeclines as nicotine loadings of the patches decline.

Examples 29-31

The blood levels shown in FIG. 5 were obtained from 6 adult male smokerswho had already developed a strong tolerance to nicotine. For allexamples, transdermal nicotine systems used were manufactured asdescribed in Examples 24-27, and each contained a total of 37 mgnicotine in a patch with an area of 5 cm², as in Example 24. For Example28, a single 5 cm² transdermal nicotine patch was applied to the rightforearm of each subject, and the patch remained affixed to the forearmfor 16 hours. The lowest curve presents the average nicotine plasmalevel obtained. For Example 29, two 5 cm² transdermal nicotine patcheswere applied to the right forearm of each subject, and the patchesremained affixed to the forearm for 16 hours. The middle curve presentsthe average nicotine plasma levels obtained. For Example 30, three 5 cm²transdermal nicotine patches were applied to the right forearm of eachsubject, and the patches remained affixed for 16 hours. The top curvepresents the average nicotine plasma levels obtained. These testsubjects were able to tolerate as many as three 5 cm² patches with atotal in vitro delivery of almost 70 mg/24 h without any untowardsymptoms.

Example 32 In Vivo Studies

In vivo studies have been conducted to establish the bioavailability ofnicotine from the transdermal patches of the present invention. Thestudy, employing 12 healthy male smokers, consisted of three treatmentperiods which were run in a balanced crossover design to compare thesteady state pharmacokinetics of the 22 and 27 mg patches of the presentinvention with the PROSTEP 22 mg transdermal nicotine patch, availablefrom elan pharma, Ltd., Athlone, County Westmeath, Ireland, andmanufactured by Lederle Laboratories Division, American CyanamidCompany, Pearl River, N.Y.

After a 60 hour run-in phase, the nicotine patches were worn for a 24hour period for each of the five consecutive days of the treatmentperiod. The resulting blood plasma levels, along with those of thePROSTEP 22 mg patch are shown in FIG. 14. The patches of the presentinvention were well tolerated.

The steady-state parameters for currently marketed nicotine transdermalsystems are summarized in Table VI below.

                  TABLE VI                                                        ______________________________________                                        Transdermal                                                                             Cmax.sup.6                                                                             Cavg.sup.7                                                                              Cmin.sup.8                                                                            Tmax.sup.9                               Patch.sup.5                                                                             (ng/mL)  (ng/mL)   (ng/mL) (hrs)                                    ______________________________________                                        Habitrol ™                                                                           17 ± 2                                                                              13 ± 2 9 ± 2                                                                              6 ± 3                                 (21 mg/day).sup.10                                                            PROSTEP ™                                                                            16 ± 6                                                                              11 ± 3 5 ± 1                                                                              9 ± 5                                 (22 mg/day)                                                                   NICODERM .SM.                                                                           23 ± 5                                                                              17 ± 4 11 ± 3                                                                             4 ± 3                                 (21 mg/day)                                                                   NICOTROL .SM.                                                                           13.0 ± 3.1                                                                           8.7 ± 2.1                                                                           2.5 ± 0.8                                                                          8 ± 3                                 (15 mg/day)                                                                   PATCH OF  16.1 ± 7.1                                                                          11.2 ± 4.1                                                                           4.8 ± 1.8                                                                          8.4 ± 1.8                             EXAMPLE 1                                                                     (22 mg/day)                                                                   PATCH OF  23.4 ± 8.1                                                                          14.5 ± 3.3                                                                           5.7 ± 1.9                                                                          8.4 ± 3.3                             EXAMPLE 2                                                                     (27 mg/day)                                                                   ______________________________________                                         .sup.5 Competitor product data taken from product inserts.                    .sup.6 Cmax = maximum observed plasma concentration.                          .sup.7 Cavg = average plasma concentration                                    .sup.8 Cmin = minimum observed plasma concentration                           .sup.9 Tmax = time of maximum plasma concentration                            .sup.10 Available from BASEL Pharmaceuticals, a division of CIBAGEIGY         Corporation, Summit, NJ.                                                 

Example 32 Buffered Nicotine Sublingual Tablet

    ______________________________________                                        FORMULATION                                                                   Ingredient         mg/tablet                                                  ______________________________________                                        Nicotine free base 2.0                                                        Microcrystalline cellulose.sup.11                                                                50.0                                                       Magnesium stearate 2.6                                                        Colloidal silica.sup.12                                                                          5.0                                                        Gum arabic         4.0                                                        Polyvinyl alcohol  1.2                                                        Starch             53.0                                                       Mannitol           32.0                                                       Lactose            38.4                                                       Sucrose            137.0                                                      Disodium hydrogen phosphate                                                                      9.7                                                        Citric acid        0.3                                                        Mint flavor.sup.13 4.0                                                        Ammonium glycyrrhizinate.sup.14                                                                  4.0                                                        ______________________________________                                         .sup.11 Avicel PH 101                                                         .sup.12 Aerosil 200                                                           .sup.13 Pulvaromas mint                                                       .sup.14 Glycamil                                                         

Manufacturing Method-Granulation

1. Avicel PH 101 and Aerosil 200 are well mixed in a Turbula mixer forat least 10 min.

2. Nicotine is adsorbed onto the blend obtained in Step 1., which actsas a carrier. This is accomplished by very carefully mixing nicotine ina mortar with half the quantity of the blend. When a good dispersion isobtained, the remaining quantity is added and mixed well until ahomogeneous dispersion is achieved.

3. A granulate is then prepared by mixing in a Tonazzi kneading machinegum arabic, polyvinyl alcohol, mannitol, starch, disodium hydrogenphosphate, citric acid, lactose, and sucrose. Water is used as agranulating liquid.

4. The mixture obtained is then granulated using an Alexanderwerkgranulator equipped with a No. 2 screen.

5. The granulate is dried in a Buhler oven with circulating air at 50°C. up to a moisture content of 3%.

6. using a Turbula mixer, the dispersion of nicotine onto Avicel PH 101and Aerosil 200 is mixed with the granulate obtained in Step 5. for atleast 15 min.

7. Magnesium stearate, Pulvaromas mint, and Glycamil are added in theTurbula mixer and mixed with the blend obtained in Step 6. for at least15 min.

8. The blend of powders is compressed using single punch tablet pressequipped with a 9 mm diameter biconvex punch, obtaining tablets with aweight of 343.2 mg and hardness of 15 Kp.

Example 33 Buffered Nicotine Sublingual Capsule (Chewable Soft GelatinCapsules)

    ______________________________________                                        FORMULATION                                                                   Ingredient         mg/tablet                                                  ______________________________________                                        Nicotine free base 2.0                                                        Glycerol           20.40                                                      Water              34.00                                                      Sodium saccharinate                                                                              0.50                                                       Polyethylene glycol.sup.15                                                                       386.00                                                     Mint flavor.sup.16 0.70                                                       Ammonium glycyrrhizinate.sup.17                                                                  0.70                                                       Disodium hydrogen phosphate                                                                      12.90                                                      Citric acid        0.40                                                       ______________________________________                                         .sup.15 Carbowax 400                                                          .sup.16 Pulvaromas mint                                                       .sup.17 Glycamil                                                         

Procedure

1. Glycerol, water, sodium saccharinate, and Carbowax 400 are mixed in astainless steel reactor for at least 15 min.

2. Disodium hydrogen phosphate and citric acid are added and mixed forat least 10 min.

3. While stirring well, nicotine, Pulvaromas, and glycamil are added.The mixture is stirred for at least 15 min.

4. The mixture obtained in Step 2. is transferred to a stainless steelcontainer.

5. The following shell constituents are introduced into a stainlesssteel container: gelatin, glycerin, titanium dioxide, sodium ethylhydroxybenzoate, and sodium propyl hydroxybenzoate. (For a capsulecontent of 450 mg, typical quantities of shell constituents would begelatin-140 mg, glycerin-67 mg, titanium dioxide-2.8 mg, sodium ethylhydroxybenzoate-0.6 mg, and sodium propyl hydroxybenzoate-0.5 mg.) Theyare melted at 70° C. The mixture is stirred for 15 min. to make ithomogeneous.

6. The Pulvaromas mint is added to the melted mixture for the shell andstirred for 2 min.

7. The Scherer capsulation machine is filled with the melted mixtureobtained in Step 6.

8. The capsules are produced in the predetermined shape and volume, andthe solution obtained in Step 3. is injected inside them by means ofspecial nozzles.

Example 34 Nicotine Lozenge

    ______________________________________                                        FORMULATION                                                                   Ingredients        mg/tablet                                                  ______________________________________                                        Nicotine           1.0                                                        Mannitol           200.0                                                      Xylitol            1309.0                                                     Mint flavor        20.0                                                       Ammonium glycyrrhizinate                                                                         15.0                                                       Sodium carbonate   5.0                                                        Sodium bicarbonate 15.0                                                       Hydrogenated vegetable oil                                                                       25.0                                                       Magnesium stearate 10.0                                                       ______________________________________                                    

Procedure

1. Nicotine was dispersed in mannitol.

2. The powders were mixed.

3. The mixture was compressed with a suitable alternative tablet press,using a square 16 mm-punch dosing 1600 mg/tablet.

4. Tablets were packed into strips of aluminum/Barex.

Example 35

    ______________________________________                                        FORMULATION                                                                   Ingredients        mg/tablet                                                  ______________________________________                                        Nicotine           1.0                                                        Mannitol           200.0                                                      Xylitol            1316.5                                                     Tobacco flavor     6.0                                                        Colloidal silica   1.5                                                        Ammonium glycyrrhizinate                                                                         15.0                                                       Sodium carbonate   5.0                                                        Sodium bicarbonate 15.0                                                       Hydrogenated vegetable oil                                                                       30.0                                                       Magnesium stearate 10.0                                                       ______________________________________                                    

Procedure

1. Nicotine was dispersed in mannitol.

2. The powders were mixed.

3. The mixture was compressed with a suitable alternative tablet press,using a square 16 mm-punch dosing 1600 mg/tablet.

4. Tablets were packed into strips of aluminum/Barex.

Example 36 Nicotine Lozenge

    ______________________________________                                        FORMULATION                                                                   Ingredients        mg/tablet                                                  ______________________________________                                        Nicotine           1.0                                                        β-cyclodextrin                                                                              109.0                                                      Water              10.0                                                       Xylitol            1400.0                                                     Mint flavor        20.0                                                       Ammonium glycyrrhizinate                                                                         15.0                                                       Sodium carbonate   5.0                                                        Sodium bicarbonate 15.0                                                       Hydrogenated vegetable oil                                                                       25.0                                                       Magnesium stearate 10.0                                                       ______________________________________                                    

Procedure

1. Nicotine was dispersed in β-cyclodextrin.

2. The powders were mixed.

3. The mixture was compressed with a suitable alternative tablet press,using a square 16 mm-punch dosing 1600 mg/tablet.

4. Tablets were packed into strips of aluminum/Barex.

Example 37

Manufacturing Process for Nicotine Lozenge Formulation with Xylitol,Mannitol, and Mint Flavor

1. Preparation of the nicotine-mannitol mixture

One kg of mannitol was sieved through a 50 mesh sieve and was placed ina Tonazzi mixer. Next, 10 g of nicotine were added slowly with mixingfor 10 minutes. The mixture was transferred to a 2 liter amber glassbottle and mixed for 15 minutes in a Turbula mixer.

2. Preparation of the granulate

A quantity of 50.5 g of the mixture from (1) above and 54.5 g of Xilitab200 (xylitol) were sieved with a 20 mesh sieve, and then were mixed with50 g mannitol, 5 g magnesium stearate, 12.5 mg Lubritab (hydrogenatedvegetable oil), 10 g mint flavor, 7.5 g ammonium glycyrrhizinate, 7.5 gsodium bicarbonate, and 2.5 g sodium carbonate, and was sieved through a50 mesh sieve. The mixture was transferred to a 2 liter amber glassbottle and mixed for 15 minutes in a Turbula mixer.

3. Tablet formation

The mixture was tabletted in a Belloni alternative press, using a 16-mm²punch. Tablet weight was 1600 mg/tablet.

4. Packaging

The tablets were packaged into strips of paper/aluminum/Barex.

Example 38

Manufacturing Process for Nicotine Lozenge Formulation with Xylitol,β-Cyclodextrin, and Mint Flavor

1. Preparation of the nicotine--β-cyclodextrin complex

An initial quantity of 56.76 g of β-cyclodextrin was placed in a 400 mLbeaker and 5.68 g of H₂ O (equivalent to 10% of the powder) was addedwith stirring. The water was added in amounts of 1.9 g at a time, withstirring for 10 minutes at each step. The powder, before addition ofnicotine, was similar to a wet granulate.

Next, 6.37 g of nicotine was added very slowly with stirring, and at theend of the process the granulate was stirred for 15 minutes. Theobtained granulate was dried in an oven at 35° C. for 2 hours.

A sample was then analyzed for nicotine content.

2. Preparation of the dry granulate

A quantity of 5.25 g of the nicotine--β-cyclodextrin complex, 50 g ofβ-cyclodextrin, 5 g magnesium stearate, 12.5 g Lubritab® (hydrogenatedvegetable oil), 10 g mint flavor, 7.5 g ammonium glycyrrhizinate, 7.5 gsodium bicarbonate, and 2.5 g sodium carbonate were sieved through an 80mesh sieve.

Next,. 700 g of Xilitab® 100 (xylitol) was sieved through a 50 meshsieve.

The mixture was mixed in a Turbula mixer for 20 minutes.

3. Tablet formation

The mixture from (2) above was tabletted with a Belloni tablet pressequipped with square punches. Tablet weight was 1600 mg/tablet.

4. Packaging

The tablets were put in strips of paper/aluminum/Barex having thefollowing composition: paper 50 g/m², aluminum 12 μ thickness, 32 g/m²,Barex 35 g/m².

Example 39 Nicotine Lozenge Stability Assay

One nicotine lozenge was crushed and placed in a 50 mL volumetric flask.To the flask was then added tetrahydrofuran (25 mL) and the flask wastransferred to a sonicating bath where it was allowed to stand for 20minutes. Sufficient ethyl acetate was added to bring the volume ofsolution up to 50 mL. A portion of this solution (1 mL) was removed andplaced in a 25 mL volumetric flask. To this flask was then added a fewmilliliters of water and 0.25 mL of an internal standard solutionconsisting of 50 mg acetanilide diluted to 100 mL with water. Theorganic solvents were removed using a gentle nitrogen gas flow whichresulted in a cloudy solution. Sufficient water was then added to thecloudy solution to bring the volume of the solution to 25 mL. Thesolution was then filtered through a 0.22 mcm membrane.

The amount of nicotine in the sample was determined using highperformance liquid chromatography (column temperature, 30±1° C.; mobilephase, water:methanol:acetate buffer (0.1M, pH=4.0):acetonitrile60:31:7:2, adjusted to pH=6.82 with triethylamine, filtered, anddeaerated; mobil phase flow rate, 1.0 mL/min; solid phase, SupelcosilLC1808 (5 mcm) 25 centimeters (cm)×4.6 millimeters (mm), available fromSupelco Inc.; and analytical wavelength 254±1 nanometers (nm)). Underthese conditions, nicotine and acetanilide had retention times of about7.7 and 9.3 minutes, respectively. The ratio of the components in themobile phase can be varied to provide suitable elution times for thenicotine and the internal standard.

Example 40 In Vivo Measurement of Nicotine Release from a Lozenge

A clinical trial of the lozenge described in Example 32 involves sixpatients who are each given one lozenge on study day 1 at 8:00 a.m. Apre-dose blood sample is taken before each administration. The patientsare asked to suck the lozenge. Blood samples are taken at 2.5, 5, 7.5,10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120, and 240 minutes. Inaddition, immediately after the lozenge has dissolved, the patientnotifies the medical staff so that the time of dissolution can berecorded.

Blood samples of 5 mL are collected in lithium heparinate tubes.Immediately after collection, the samples are cooled and centrifuged at4° C. at 1500 rpm for 15 minutes. The plasma is then transferred topolypropylene tubes and stored at -30° C. until analysis for nicotineand cotinine. A capillary gas chromatographic method is used for theanalysis of nicotine and cotinine. The detection limit is 0.8 ng/mL fornicotine and 5.0 ng/mL for cotinine. The quantitative determinationlimit is 1.0 ng/mL for nicotine and 10 ng/mL for cotinine.

The disclosures in this application of all articles and references,including patent documents, are incorporated herein by reference.

It is to be understood that the above description is intended to beillustrative and not restrictive. Many embodiments will be apparent tothose of skill in the art upon reviewing the above description. Thescope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

What is claimed is:
 1. A method for treating a condition responsive tonicotine therapy, comprising the steps of:i) a first treatment withnicotine by transdermal administration to obtain nicotine blood levelsof between 5 to 35 ng/mL for at least 12 hours; and ii) a secondtreatment with nicotine by transmucosal administration through the nasalmembranes by the administration of an aerosol formulation to obtainmaximum nicotine blood levels from 2 to 20 minutes after thetransmucosal administration; andwherein the transmucosa administrationprovides transient blood levels of nicotine about 5 ng/mL above thatprovided by the transderma administration of nicotine.
 2. The method asdescribed in claim 1, wherein the transmucosal administration throughthe nasal membranes is obtained by the administration of an aerosolformulation in the form of a nasal spray and results in maximum nicotineblood levels from 2 to 10 minutes after the transmucosal administrationof nicotine.
 3. The method of claim 2, wherein the range ofconcentration of the nicotine in the nasal spray is generally within therange of 0.1-100 mg/mL.
 4. The method of claim 2, whereto the range ofconcentration of the nicotine in the nasal spray is generally within therange of 1-10 mg/mL.
 5. A combination of a system for transdermaladministration of nicotine and a system for transmucosal administrationof nicotine for use, wherein:a) the system for transdermaladministration comprises:i) a nicotine depot layer, having a skin-facingside and a skin-distal side, the depot layer containing a sufficientquantity of nicotine to maintain a useful flux of nicotine from thepatch for a total time period of 12 hours or more; ii) an occlusivebacking layer in contact with and covering the depot layer on theskin-distal side; and iii) rate-controlling means for controllingdiffusion of nicotine from the skin-facing side at a first flux ofgreater than zero but less than 2 mg/cm² in any hour for a first timeperiod of greater than zero but less than 5 hours, then at a second fluxbetween 20 and 800 mu g/cm² h for a second time period of 7 hours ormore,wherein the transdermal system results in nicotine blood levels ofbetween 5 to 30 ng/mL for at least 12 hours; and b) the system fortransmucosal administration of nicotine is through the nasal membranesand is obtained by the administration of a nasal spray which providestransient blood levels of nicotine about 5 ng/mL above that provided bythe transdermal administration of nicotine when the transdermal andtransmucosal administration of nicotine is concurrent.